Type 1/Type 2 Immunity in Infectious Diseases - Clinical Infectious

76 • CID 2001:32 (1 January) • Spellberg and Edwards

R E V I E W A R T I C L E

Type 1/Type 2 Immunity in Infectious Diseases

Brad Spellberg1 and John E. Edwards, Jr.1,2

1Department of Internal Medicine and 2Division of Infectious Diseases, Harbor–University of California Los Angeles Medical Center, Torrance,California

T helper type 1 (Th1) lymphocytes secrete secrete interleukin (IL)-2, interferon-g, and lymphotoxin-a and

stimulate type 1 immunity, which is characterized by intense phagocytic activity. Conversely, Th2 cells secrete

IL-4, IL-5, IL-9, IL-10, and IL-13 and stimulate type 2 immunity, which is characterized by high antibody

titers. Type 1 and type 2 immunity are not strictly synonymous with cell-mediated and humoral immunity,

because Th1 cells also stimulate moderate levels of antibody production, whereas Th2 cells actively suppress

phagocytosis. For most infections, save those caused by large eukaryotic pathogens, type 1 immunity is

protective, whereas type 2 responses assist with the resolution of cell-mediated inflammation. Severe systemic

stress, immunosuppression, or overwhelming microbial inoculation causes the immune system to mount a

type 2 response to an infection normally controlled by type 1 immunity. In such cases, administration of

antimicrobial chemotherapy and exogenous cytokines restores systemic balance, which allows successful im-

mune responses to clear the infection.

HISTORICAL BACKGROUND

At the turn of the 20th century, the new science of

immunology was in the throes of a fundamental debate:

were phagocytic cells the keys to protection against in-

fection, as proposed by Metchnikoff [1], or were hu-

moral antibodies the true protective factors, as

forwarded by Koch’s students, von Behring and Ehrlich

[2]? Although the humoralists at first carried the day,

the joint awarding of the 1908 Nobel Prize in Medicine

to the opponents, Metchnikoff and Ehrlich, was pro-

phetic. By the end of the century, the opposing theories

created by these two fathers of immunology would be

unified in one paradigm of host defense against infec-

tion: type 1/type 2 immunity.

The terms type 1 and type 2 immunity bear no re-

lation to types 1–4 of hypersensitivity reactions de-

Received 13 April 2000; revised 2 August 2000; electronically published 15December 2000.

Financial support: National Institutes of Health / National Insititute of Allergyand Infectious Diseases (grants RO1 AI19990 and PO1 AI37194), University ofAlabama Clinical Trials of Antifungal Therapies, and Bristol Meyers Squibb Award.

Reprints or correspondence: Dr. Brad Spellberg, Dept. of Medicine, Harbor-UCLAMedical Center, 1000 West Carson St., Torrance, CA 90509 ([email protected]).

Clinical Infectious Diseases 2001; 32:76–102Q 2001 by the Infectious Diseases Society of America. All rights reserved.1058-4838/2001/3201-0012$03.00

scribed by Gell and Coombs [2a]. Rather, the birth of

the type 1/type 2 immunity paradigm can be traced to

landmark articles by Parish in the early 1970s [3–5].

Building on studies of immune regulation by Sercarz

and Coonz [6], Dresser [7, 8], and Mitchison [9], Parish

described a striking inverse correlation between the de-

gree to which a given dose of antigen elicited antibody

production or delayed type hypersensitivity (DTH; fig-

ure 1). His results, confirmed by other investigators

utilizing different experimental models [10–12], were

the bedrock of what would become the type 1/type 2

hypothesis: the level of antibody elicited in an immune

response is inversely proportional to the level of cell-

mediated immunity.

Given the link between humoral and cell-mediated

immunity, there was much interest in characterizing

the regulation of these alternate forms of host defense.

By the early 1980s the 2 major subsets of T lymphocytes

had been described: T helper cells, which express the

surface protein CD4, and T-cytotoxic cells, which ex-

press the CD8 marker (figure 2). Whereas CD81 T-

cytotoxic lymphocytes were known to mediate lysis of

autologous cells infected by intracellular pathogens,

CD41 T helper cells were known to induce B cell pro-

duction of antibodies. Their stimulation of antibody

responses made T helper cells the natural subjects of

Dow

nloaded from https://academ

ic.oup.com/cid/article/32/1/76/311106 by guest on 20 January 2022

Immunity in Infection • CID 2001:32 (1 January) • 77

Figure 1. Murine humoral and cell-mediated immune (CMI) responsesto a broad range of Salmonella flagellin doses are inversely related.Humoral response is quantified by antibody titer, whereas CMI responseis quantified by the footpad-swelling reaction, a form of delayed-typehypersensitivity (figure reproduced with permission from [3]).

investigations into the common regulation of humoral and cell-

mediated immunity.

It was in an effort to elucidate the role of T helper lympho-

cytes in induction of the DTH reaction that Mosmann et al.

[13] first described the existence of subpopulations of CD4

cells known as T helper type 1 (Th1) and T helper type 2 (Th2)

lymphocytes. By assaying cytokine production of CD41 T

helper cells from inbred mice, the investigators were able to

divide the T cell clones into 2 phenotypes. Th1 cells produced

IL-2, IFN-g, and lymphotoxin (LT)-a. Conversely, Th2 cells

produced IL-4 as well as other cytokines that had yet to be

characterized. Both Th1 and Th2 cells provided help to B cells

in antibody assays, but, as reported by Cher and Mosmann a

year later, only Th1 cells, and not Th2 cells, could elicit DTH

in mice [14].

TH1/TH2 CELL BIOLOGY

Definitions. Th1 and Th2 cells are now known to exist in

human beings as well as mice [15, 16]. All T helper lymphocytes

start out as naive Th0 cells, which, after being activated, are

capable of “polarizing,” or differentiating, into either Th1 or

Th2 effector cells [17, 18]. Mature Th1 cells secrete IL-2, IFN-

g, and LT-a, and Th2 cells secrete IL-4, IL-5, IL-9, IL-10, and

IL-13 [19, 20] (some investigators include IL-6, although this

is controversial [21, 22]). In humans this division is not as

stringent as in inbred mice. For example, some human Th1

cells secrete IL-10 [23] and IL-13 [24]. In part because of such

an overlap of cytokine secretion, the conventional definition

of a Th1 or Th2 cell depends strictly on the secretion of IFN-

g or IL-4. Th1 cells secrete IFN-g but do not secrete IL-4,

whereas Th2 cells secrete IL-4 but not IFN-g. T cells secreting

neither IFN-g nor IL-4 are neither Th1 nor Th2 cells. Some

of these cells are naive Th0 lymphocytes that have never before

been activated and thus have not acquired the ability to secrete

a mature profile of cytokines.

Aside from Th1 and Th2 cells, several other subtypes of T

helper cells have been described (table 1), and indeed the fre-

quency of polarization to the Th1 or Th2 phenotype in vivo

is controversial [30, 31]. Like naive T cells, mature T cells

secreting both IFN-g and IL-4 are also known as Th0 cells,

which can lead to some confusion. These latter Th0 cells are

lymphocytes that did not polarize during maturation and thus

took on attributes of both Th1 and Th2 cells [32, 33]. Addi-

tional populations of CD41 T helper lymphocytes called Th3

cells and T-regulatory 1 (Tr1) cells have been described. Th3

cells secrete transforming growth factor (TGF)-b and are

thought to regulate mucosal immunity in mammals [34–37].

Tr1 cells, which appear to be similar to Th3 cells, secrete un-

usually high levels of IL-10 and also lower levels of TGF-b, and

they have been implicated in general suppression of immunity

[38, 39]. Th3 and Tr1 cells are beyond the scope of this review,

which will focus on Th1 and Th2 cells, the crucial cell types

in defining the type 1/type 2 paradigm.

Effects of Th1 and Th2 cells. Th1 cells are the principal

regulators of type 1 immunity. The cytokine chiefly responsible

for their proinflammatory effect is IFN-g. IFN-g stimulates

phagocytosis [40, 41], the oxidative burst [42, 43], and intra-

cellular killing of microbes [44–46]. IFN-g also upregulates

expression of class I [47, 48] and class II major histocompat-

ibility complex (MHC) molecules [49, 50] on a variety of cells,

thereby stimulating antigen presentation to T cells (figure 2).

Both IFN-g and LT-a induce other cell types, including non-

leukocytes such as endothelial cells [51], keratinocytes [52],

and fibroblasts [53, 54], to secrete proinflammatory cytokines,

such as TNF and chemotactic cytokines called chemokines [55].

They also stimulate adhesion molecule expression on endo-

thelial cells and induce endothelial cell retraction and vascular

smooth-muscle relaxation. The result is accumulation of blood

in dilated, leaky vessels, easing diapedesis of leukocytes into

areas of danger and allowing recruitment of innate immune

cells and opsonins into the interstitium. Thus Th1 cells cause

rubor (redness), tumor (swelling), dolor (pain), and calor

(warmth), the 4 cardinal signs of inflammation.

Th2 cells, conversely, stimulate high titers of antibody pro-

duction. In particular, IL-4, IL-10, and IL-13 activate B cell

proliferation, antibody production, and class-switching [56–

58]. In fact, class-switching from IgG to IgE cannot occur with-

out the presence of IL-4 or IL-13 [59–61], making the pro-

duction of IgE a perfect bioassay for the presence of Th2 cells

in vivo. IL-5 is a potent hematopoietic cytokine that stimulates

bone marrow production of eosinophils [62–64], as well as

activation and chemotaxis of eosinophils [65, 66] and basophils

[67, 68], whereas IL-9 is the equivalent hematopoietic and stim-

ulatory factor for mast cells [69, 70]. It is interesting that IL-

Dow




Figure 2. Antigen presentation to T-cytotoxic (CD81) and T helper (CD41) cells. In A, a host cell is (1) infected by an intracellular pathogen (avirus, in this example). (2) As progeny virions are produced, viral antigens are pumped into the endoplasmic reticulum, where they bind to class Imajor histocompatibility complex (MHC I) proteins. (3) Covalent interaction with the chaperone protein, b-2 microglobulin (b-2M), allows surfaceexpression of the MHC I polypeptide, which presents viral antigen bound to a groove at its tip. The CD8 protein on the T-cytotoxic cell binds to theMHC I molecule, stabilizing the interaction between the T-cell receptor (TCR) and the MHC I–antigen complex. (4) The result is activation of the T-cytotoxic cell, which then lyses the host cell to expose the intracellular virus. In B, a phagocyte (1) ingests extracellular microbes and degrades themin the phagolysosome. (2) Degraded microbial fragments are loaded onto class II MHC molecules in the phagolysosome, and the MHC II–antigencomplexes are transported to the cell surface. (3) CD4 binds to MHC II, stabilizing the interaction between the TCR and the MHC II–antigen complex.(4) The result is activation of the T helper cell, which then autocrine-stimulates its own proliferation by secreting IL-2.

4, IL-5, IL-9, and IL-13 have been strongly implicated in allergic

and atopic reactions, as well as in causing the airway inflam-

mation seen in asthma and reactive airway disease [71–78].

Unlike inflammation stimulated by type 1 cytokines, type

2–mediated inflammation is characterized by eosinophilic and

basophilic tissue infiltration, as well as extensive mast cell de-

granulation, a process dependent on cross-linking of surface-

bound IgE.

In addition to their stimulatory effects, Th1 and Th2 cells

cross-regulate one another. The IFN-g secreted by Th1 cells

directly suppresses IL-4 secretion and thus inhibits differenti-

ation of naive Th0 cells into Th2 cells [79–81]. Conversely, IL-

4 and IL-10 inhibit the secretion of IL-12 and IFN-g, blocking

the ability of Th0 cells to polarize into Th1 cells [82–84]. IL-

10 is perhaps the most anti-inflammatory cytokine known [85].

It inhibits the secretion of proinflammatory cytokines [86, 87];

suppresses phagocytosis [88], the oxidative burst [89, 90], and

intracellular killing [91, 92]; and inhibits antigen presentation

to T cells [93, 94], causing T cell anergy [95]. Like IL-10, IL-

4 and IL-13 also inhibit phagocytosis and intracellular killing

[91, 92], suppress inflammatory cytokine production [96], and

may induce T cell anergy [97].

There are also differences in proliferation requirements be-

tween Th1 and Th2 cells. Naive T cells and Th1 cells absolutely

require IL-2 for activation and proliferation [98]. However, Th2

cells are perfectly capable of proliferating without IL-2 if IL-4

[98, 99] and/or IL-1 [100, 101] is present, which is convenient

for them since they secrete large quantities of IL-4. Therefore,

in clinical situations where IL-2 is in limited supply (for ex-

ample, in patients taking cyclosporine or FK-506 or high-dose

glucocorticoids), only Th2 cells will be able to proliferate in

response to antigenic exposure.

TH1 AND TH2 REGULATION

Five Factors Inducing Polarization

Five factors regulate the polarization of newly activated naive

T cells into mature Th1 or Th2 cells [19, 102]: the local cytokine

milieu; the presence of immunologically active hormones; the

dose and route of antigen administration; the type of antigen-

Dow




Table 1. Subtypes of CD4+ T-helper (Th) cells and their characteristic cytokines and effects.

Subtype Defining cytokines Effect(s)

Naive Th0 IL-2 Proliferate and differentiate to effector cells

Th1 IL-2, IFN-g, lymphotoxin-a Cell-mediated immunity, opsonizing antibody

Mature Th0 IFN-g, IL-4, others Unclear

Th2 IL-4, IL-5, IL-9, IL-10, IL-13 Humoral immunity, inhibits inflammation

Th3 TGF-b Regulates mucosal immunity and srimulatesB cell secretions of IgA

T-regulatory 1a High levels of IL-10, some TGF-b Supression of immune response

NOTE. TGF, transforming growth factor.a T-regulatory 1 cells may represent one form of the long-elusive T-suppressor cell [25]. Although the concept

of T-suppressor cells has been discredited [26, 27], recent data have implicated both CD41 T-regulatory 1 cells anda separate population of CD41 CD251 T-helper cells in antigen-specific immunosuppression [28]. In the past, CD81

T-cytotoxic cells were widely referred to as T-suppressor cells, especially in the context of AIDS [29]; however,there is no evidence that CD8 cells are inherently suppressive, and use of the term “T-suppressor” to describeCD8 cells should be abandoned.

presenting cell stimulating the T cell; and the “strength of sig-

nal,” which is an ill-defined summation of the affinity of the

T-cell receptor for the MHC-antigen complex, combined with

the timing and density of receptor ligation. Of these 5 factors,

the most important is the cytokine milieu surrounding the

newly activated T cell.

Cytokines. The key to polarization into the Th1 phenotype

is IL-12 [103–106]. Conversely, IL-4 is the sine qua non for

Th2 polarization [107–110]. Recent studies have indicated that

the phenotype of a newly activated T cell is determined within

48–72 h after activation [110, 111]. This correlates with the in

vivo finding that T cells activated in lymph nodes do not po-

larize until they are exposed to specific cytokine milieus after

traveling to peripheral effector sites, which occurs 2–3 days

following activation [112]. Thus Th1 or Th2 polarization may

not occur until an activated T cell arrives at the site of danger

and samples the local cytokine milieu to determine if an in-

flammatory or antibody response is appropriate. T cells exposed

to IL-12 during this time differentiate to become Th1 cells, and

T cells exposed to IL-4 differentiate to become Th2 cells. When

the immune system is “in doubt” about whether Th1 or Th2

cells should be generated, Th2 outcomes are favored. For in-

stance, if both IL-12 and IL-4 are present at the time of T cell

activation, the effect of the IL-4 dominates, and the T lym-

phocytes polarize to become Th2 effectors [103, 104, 113].

Whether or not established Th1 and Th2 clones can be made

to reverse their phenotypes is controversial [113, 114], but it

is known that the responses of both Th1 and Th2 cells are

reversible at the population level [115, 116], which presents

something of a conundrum. If individual T cell clones are nearly

impossible to reverse, how can the response of an entire pop-

ulation of T cells be reversed? The answer is that even in highly

polarized T cell populations, quiescent clones of the phenotype

opposite to the dominant response can be found by fluores-

cence-activated cell-sorting (FACS) or limiting dilution anal-

ysis. That is, quiescent Th1 cells can be found in populations

secreting large amounts of IL-4 and IL-10, and quiescent Th2

cells can be found in populations secreting IFN-g and IL-2

[117–119]. Reversal of a population response involves inhib-

iting the dominant clones and allowing expansion of the qui-

escent clones by modulating the cytokine environment.

Therefore, the nature of an immune response cannot be

reliably determined from cytokine patterns of individual T cell

clones, which may or may not be representative of the dominant

population phenotype. Furthermore, B cells, phagocytes, and

even nonleukocytes can secrete cytokines typical of a Th1 or

Th2 cell (e.g., IFN-g, IL-4, and IL-10). For these reasons, the

terms “Th1 response” and “Th2 response,” which imply only

measurement of responses by T helper cell clones, are insuf-

ficient. Instead, as originally proposed by Clerici and Shearer

in the context of HIV [120], the terms “type 1 response” and

“type 2 response” should be used to indicate a summation of

the systemic response to a given infection (i.e., a type 1 response

is characterized by high in vivo production of the Th1 cytokines

IL-2, IFN-g, and LT-a, without implying that these cytokines

are exclusively being produced by T helper cells).

Hormones. Glucocorticoids are powerful stimulators of

type 2 outcomes and powerful inhibitors of type 1 outcomes,

directly inducing IL-4 and IL-10 production from lymphocytes

and antigen-presenting cells [121–123] while suppressing the

secretion and effects of IFN-g and IL-12 [124–127]. Further-

more, they suppress secretion of IL-2 [128, 129], which inhibits

activated Th1 cells from proliferating while allowing Th2 cells

to expand. It is interesting that at high concentrations, glu-

cocorticoids induce lympholysis [130] and inhibit all cytokine

secretion, including type 2 cytokines [131, 132]. In order to

suppress lymphocyte proliferation and type 2 cytokine pro-

duction in vitro, glucocorticoids must be present at at least

1027 M concentrations [132–134]. Although direct comparison

with in vivo serum concentrations is problematic, it has been

Dow




estimated that serum glucocorticoid levels must reach ∼1026

M to be clinically effective in reactive airways disease [135].

A study of patients receiving iv prednisolone indicated that

a dose of 1 mg/kg markedly diminished serum T cell concen-

trations and ex vivo cytokine production, whereas a dose of

0.1 mg/kg mediated minimal changes in serum T cell counts

and cytokine production [136]. Thus, at doses used clinically

(∼40–60 mg of methylprednisolone per day), serum cortisol

levels exceed those required to suppress type 2 cytokine secre-

tion, a circumstance that probably explains the efficacy of ster-

oid pulses in the treatment of reactive airways disease.

Like glucocorticoids, estrogens and progestins have been

shown to suppress type 1 immunity in favor of type 2 immunity.

Both estrogens and progestins inhibit IL-12 and IFN-g secretion

from antigen-presenting cells and T cells, while stimulating IL-

4, IL-10, and IL-13 secretion [137–139]. The persistence of the

allogeneic fetus in its pregnant mother is perhaps the most

compelling example of immunologic tolerance known. Placen-

tal secretion of estrogens, progestins, IL-4, and IL-10 [140, 141],

which produces type 2 responses to antigenic stimulation dur-

ing pregnancy [142], is largely responsible for this peripheral

tolerance. Aberrant regulation allowing type 1 immunity to

occur during pregnancy leads to abnormal labor [143, 144] or

maternal rejection of fetal tissues, causing abortion [145–147].

Conversely, the testosterone derivative dehydroepiandroster-

one (DHEA) has been shown to potentiate IL-2 secretion as well

as the establishment of Th1 clones [148–150]. Therefore, male

hormones favor cell-mediated immune responses, whereas fe-

male hormones favor humoral immunity. Indeed, in a direct

comparison of coxsackievirus infection in male and female mice

under identical experimental conditions, male mice mounted

type 1 responses to the virus but female mice mounted type 2

responses [151].

Perhaps the most important hormones regulating type 1 and

type 2 outcomes are the catecholamines. It has been known for

30 years that lymphocytes express catecholamine receptors

[152]. Catecholamines inhibit type 1 cytokine production [153]

and stimulate the transcription and secretion of type 2 cytokines

from a variety of leukocytes [154–158]. Furthermore, the se-

lective suppression of IL-2 production by catecholamines in-

hibits Th1 propagation, allowing selective Th2 proliferation

[159]. b-2 Agonists are extremely potent bronchodilators, a

characteristic explaining why they are acutely effective for

symptomatic asthma. However, their effects on type 2 cytokines

suggest that over the long term they might exacerbate the airway

inflammation typical of asthma, which may explain why they

must be combined with inhaled steroids to be effective as long-

term suppressive therapy.

Finally, other hormones have been shown to modulate type

1 and type 2 outcomes. Chief among these are human chorionic

gonadotropin [160], prostaglandins (PGs, especially PGE)

[161–164], and a-melanocyte–stimulating hormone [165, 166],

each of which has been shown to suppress type 1 cytokine

responses while stimulating type 2 responses.

Antigen dose. The effect of antigen dose on the polari-

zation of naive cells to Th1 or Th2 cell types is poorly under-

stood. The use of widely disparate experimental models and

an inability to correlate subjective notions of “high” versus

“low” dose ranges between these systems have led to confusion

in interpreting the literature [102]. As shall be discussed below,

however, in vivo animal data and clinical observations consis-

tently indicate that high microbial burdens suppress cell-me-

diated immunity. Therefore, consistent with Metchnikoff’s

findings at the turn of the 20th century [167], it can now be

strongly asserted that the highest dose ranges, and therefore

the highest microbial burdens in infected patients, suppress cell-

mediated immunity.

At first glance the assertion that high infectious inocula sup-

press immune responses seems counterintuitive. One might

predict that higher microbial burdens would stimulate a greater

immune response than lower microbial burdens. However, ev-

olution has adapted the mammalian host to be far more con-

cerned about auto-inflammatory destruction than tissue dam-

age wrought by microbes.

Chronic viral hepatitis proves an illuminating model in this

regard. It is known that liver necrosis in viral hepatitis is not

due to viral cytopathic effect, but rather to CD81 T-cytotoxic

lymphocytes lysing infected host cells to expose intracellular

virus [168]. Acute bursts of type 1 immunity can rapidly in-

terrupt intracellular viral replication and abort infection at the

cost of liver necrosis [169, 170]. For example, treatment with

IFN-a can lead to hepatitis virus clearance in some patients by

boosting cell-mediated immunity, leading to acute stimulation

of CD81 T-cytotoxic cell activity [171, 172]. But what if the

viral burden in the liver is very high? In such cases, the boosted

host response leads to tissue necrosis extensive enough to de-

stroy the liver and cause severe morbidity to the host in the

process of clearing the virus, a true Pyrrhic victory [173–176].

In order to prevent this, the mammalian immune system has

adapted to suppress cell-mediated immunity when the viral

load reaches a certain threshold [177]. Indeed, patients chron-

ically infected with hepatitis B virus are specifically anergic to

the virus, and lowering the viral load with lamivudine has been

shown to restore T cell–mediated antiviral effects [178].

Antigen-presenting cell. The type of antigen-presenting

cell stimulating the T cell may also play a role in the polarization

of the lymphocyte to a Th1 or Th2 phenotype [179]. Some

studies have reported that B cells are particularly prone to

inducing type 2 outcomes [180, 181], even in the presence of

IL-12 [182]. This is consistent with their need to drive a type

2 response to feed-forward stimulate their own production of

antibody. Conversely, macrophages may be more likely to stim-

Dow




ulate type 1 outcomes [183]. Dendritic cells, acknowledged to

be the most potent antigen-presenting cells in the body

[184–186], are capable of driving both type 1 and type 2 out-

comes, depending on the local cytokine microenvironment

[187].

Prostaglandins and IL-10 suppress IL-12 production by den-

dritic cells while stimulating secretion of IL-10, which leads to

Th2 polarization of responding lymphocytes [188, 189]. Con-

versely, IFN-g and microbial fractions such as lipopolysac-

charide (LPS) induce dendritic cells to secrete IL-12, stimulat-

ing type 1 outcomes [187]. On the basis of these data from

dendritic cell studies, it is now believed that all antigen-pre-

senting cells are capable of stimulating either a type 1 or type

2 outcome, depending on the presence of certain “danger sig-

nals” (see below) present in the local microenvironment [190].

Such danger signals modulate the profile of cytokines secreted

by the antigen-presenting cell, which results in polarization of

the responding lymphocyte to the Th1 or Th2 phenotype.

Strength of signal. The affinity of the T-cell receptor for

the MHC/stimulating-antigen complex, the presence of certain

costimulatory molecules on the antigen-presenting cell, and the

timing of T-cell-receptor ligation by the MHC/antigen complex

have each been shown to modify type 1 and type 2 outcomes

[191–195]. There is much confusion in this area, as evidenced

by an abundance of conflicting reports on whether high or low

affinity, present or absent costimulation, and short or long

ligation mediate Th1 or Th2 polarization. This lack of con-

cordance likely reflects study-to-study variation in the complex

interactions between these difficult-to-measure variables.

The Decision to Polarize

Having discussed the mechanisms responsible for polariza-

tion to Th1 or Th2 responses, we must now consider how the

immune system determines which outcome is superior for a

given danger signal. Since the cytokines IL-12 and IL-4 are the

key factors responsible for inducing polarization of naive T

cells toward the Th1 or Th2 profile, the question is raised: what

factors tell the immune system to preferentially produce IL-12

or IL-4 at the start of a given immune response?

In striking contrast to the prevailing notion of lymphocytes

as the “generals” of the immune response and phagocytes as

rather obtuse infantrymen, it is now clear that innate immune

cells, not T cells, make the “decision” to stimulate a type 1 or

type 2 response. Phagocytes instruct T cells to adopt a Th1 or

Th2 phenotype by secreting polarizing cytokines, thereby al-

tering the local microenvironment around the newly activated

lymphocyte. The information used by innate immune cells to

decide which cytokines to secrete include (1) the presence of

certain “danger signals” [196] in the local microenvironment

and (2) systemic factors affecting the host at the moment the

danger signals are revealed.

Microbes contain within them information that directly in-

duces secretion of IL-12 by phagocytic cells. Gram-negative

endotoxin, or LPS, and gram-positive cell wall lipotechoic acid

bind to nonpolymorphic receptors on innate immune cells and

directly induce secretion of IL-12 and other pro-inflammatory

cytokines such as IFN-a and IFN-g [197, 198]. Furthermore,

bacterial DNA is rich in immunostimulatory sequences [199].

Well-described immunostimulatory sequences include poly-G

sequences and CpG motifs [200, 201], which are hexamers of

purine-purine-CG-pyrimidine-pyrimidine. Eukaryotic DNA

contains very few CpG motifs, and even when they occur in

eukaryotic genomes they tend to be methylated. Unmethylated

prokaryotic CpG DNA is capable of directly inducing IFN-a

and -g and IL-12 secretion from B-cells, natural killer cells,

and monocyte/macrophages [202–206].

Other innately stimulatory microbial antigenic fractions have

also been described, including antigens from Toxoplasma [207],

mycobacteria [208], and fungi [197]. Finally, heat shock pro-

teins, which are synthesized in response to cellular stresses in

both prokaryotic and eukaryotic cells, are capable of directly

inducing IL-12 secretion from innate immune cells [197]. Even

host heat shock proteins induce IL-12, which indicated that the

innate immune system is genetically programmed to scan local

microenvironments for any sign of danger, even if it is an

indirect sign of host tissue destruction rather than direct evi-

dence of a microbial invader [209].

Microbial characteristics are also capable of direct induction

of type 2 immunity. When a phagocyte attempts to ingest a

particle larger than itself, the leukocyte reorganizes its cyto-

skeleton in a reaction termed “frustrated phagocytosis” [210,

211]. During this process the leukocyte exocytoses intracellular

granules that would normally have fused with the ingested

phagosome, spewing these granules toward the uningestible

particle [212, 213]. The degradative enzymes and microbial

peptides that are released are then able to damage the unin-

gestible particle. Meanwhile, genetic transcriptional changes

also occur within the innate immune cell as part of the frus-

trated phagocytosis complex of activities. There is, for example,

a marked upregulation of IL-10 secretion and a decreased se-

cretion of IL-12 in neutrophils undergoing frustrated phago-

cytosis [214]. Thus innate immune cells exposed to large ex-

tracellular pathogens, such as helminths, directly induce a type

2 cytokine environment.

Furthermore, as mentioned above, systemic host states at the

time of antigen stimulation also modulate type 1/type 2 out-

comes. Initial production of IFN-a and IFN-g by innate im-

mune cells and early responding gd T cells and natural killer

cells can also upregulate the local production of IL-12 [197,

215–218], thereby inducing a type 1 response. Conversely, pre-

existing IL-4, IL-10, and IL-13 inhibit secretion of IL-12,

thereby blocking Th1 polarization [197]. Elevated catechola-

Dow




Figure 3. Summary of Th1/Th2 induction. Cytokines, hormones, and microbial antigens stimulate the innate immune system to produce either IL-12 or IL-4 in the local microenvironment around a newly activated T cell. IL-12 induces Th0 polarization to the Th1 phenotype and inhibits polarizationto the Th2 phenotype, whereas IL-4 acts reciprocally. CMI, cell-mediated immunity; CpG, purine-purine-C-G-pyrimidine-pyrimidine DNA hexamer; DHEA,dehydroepiandrosterone; Epi/NE, epinephrine/norepinephrine; HSP, heat shock protein; LTA, lipotechoic acid; LPS, lipopolysaccharide; PG, prostaglandin;estgn/pgstn, estrogen/progesterone; frust. phag., frustrated phagocytosis.

mine, glucocorticoid, and estrogen/progesterone levels all di-

rectly suppress the development of a local cytokine milieu rich

in IL-12, and instead induce IL-4, IL-10, and IL-13. Therefore,

hosts who are undergoing physiological stress, are pregnant, or

are taking glucocorticoids, cyclosporine, or FK-506 are innately

prone to developing type 2 responses, even to antigens that

would normally elicit a type 1 response.

The Molecular Genetics of Polarization

The past 5 years have witnessed a revolution in our under-

standing of the molecular genetics of Th1/Th2 polarization.

Specifically, investigators have found that ligation of the IL-12

receptor on Th0 cells activates the transcription factor STAT4

(signal transducer and activator of transcription 4) [219], which

triggers regulatory sequences leading to Th1 polarization [220].

Conversely, ligation of the IL-4 receptor on Th0 cells triggers

activation of STAT6 [221], which suppresses Th1 polarization

and leads to Th2 polarization [222]. Indeed, mice with germline

disruptions of the STAT4 or STAT6 genes are unable to mount

type 1 [223, 224] or type 2 responses [225, 226], respectively.

Even more recently, downstream targets of STAT4 and STAT6

have been identified. The transcription factor GATA-3 directly

induces Th2 polarization and inhibits Th1 polarization, acting

in concordance with STAT6 [227–229]. Conversely, activation

of the transcription factor ERM by STAT4 induces IFN-g ex-

pression [230]. Most recently, Szabo et al. [231] identified the

penultimate effector of the STAT4-induced Th1 polarization,

the transcription factor T-bet. T-bet exerts direct control over

IFN-g gene expression, and ectopic expression of T-bet in al-

ready polarized Th2 cells redirects the lymphocytes to adopt a

Th1 profile. The reversal of phenotype of an already polarized

lymphocyte is particularly intriguing, which suggests the pos-

sibility that small molecules can be designed to disrupt the

genetic pathways controlling Th1/Th2 polarization. The de-

velopment of such agents would allow clinicians to intervene

in diseases resulting from inappropriate type 1 or type 2 im-

mune responses.

Summary

Figure 3 summarizes the processes of Th1 and Th2 induction.

Naive Th0 lymphocytes polarize into Th1 cells when they are

activated in a microenvironment rich in IL-12. IL-12 is directly

induced from innate immune cells by gram-negative LPS,

gram-positive lipotechoic acid, prokaryotic CpG DNA motifs,

and heat shock proteins, as well as pre-existing DHEA, IFN-a

and IFN-g. Conversely, IL-4, IL-10, corticosteroids and cate-

cholamines directly inhibit newly activated Th0 cells from dif-

ferentiating into Th1 cells.

Naive Th0 cells exposed to IL-4 differentiate into Th2 cells.

Exposure of innate immune cells to large, nonphagocytosable

particles induces secretion of IL-4, IL-10, and IL-13. Further-

more, any host state that leads to high levels of circulating

catecholamines, glucocorticoids, estrogens, progestins, or pros-

taglandins will directly induce secretion of IL-4, IL-10, and IL-

13 from innate cells and lymphocytes and directly suppress

secretion of IFN-g and IL-12. Exposure of naive Th0 cells to

Dow




IL-12 inhibits polarization to Th2 cells; however, if both IL-4

and IL-12 are present at the time of naive T cell activation, the

effects of the IL-4 will dominate, and a type 2 response will

ensue.

RELEVANT DISEASE MODELS: ANIMALMODELS

Type 1 Protective Models

Leishmania. The classic model of type 1/type 2 immunity

is Leishmania major infection of Balb/C or C57BL mice. Balb/

C mice are genetically prone to type 2 immune responses,

whereas C57BL mice are prone to type 1 immunity. The genetic

mechanisms of these tendencies are not well characterized, but

Balb/C mice appear to have a defect in the normal induction

of IL-12 [232], possibly due to a tendency for early hyperse-

cretion of IL-4 [233]. The result is that newly activated T cells

in Balb/C mice are resistant to Th1 polarization and instead

become Th2 cells.

Sadick and Locksley et al. first reported that Balb/C mice are

inherently susceptible to Leishmania [234, 235], and quickly

thereafter they and others showed that C57BL mice are intrin-

sically resistant to the organism [236, 237]. Subsequent studies

confirmed that CD4 cells from susceptible Balb/C mice re-

sponded to Leishmania infection by differentiating into Th2

effector cells, which could not protect the mice from infection,

whereas C57BL CD4 cells polarized into Th1 cells that abro-

gated infection [238, 239]. Blockade of IL-4 in susceptible Balb/

C mice allowed protective type 1 responses to develop, and the

mice survived the infection [239–241]. Conversely, adminis-

tration of IL-4 or abrogation of IFN-g in normally resistant

C57BL mice caused them to mount futile type 2 responses and

succumb to disseminated disease [242].

Mosmann’s group (Krishnan et al. [243]) reported that preg-

nant C57BL mice are unable to mount their normal type 1

immune responses because of placental stimulation of IL-4 and

IL-10 and suppression of IFN-g. Such pregnant mice mounted

futile type 2 responses and were unable to control Leishmania

infections. The evolutionary benefit of suppression of inflam-

mation by the pregnant state was made obvious in a second

study by the same group; induction of a type 1 response to

Leishmania in infected pregnant mice caused fetal resorption

and uterine scarring [146].

IL-12 must be present during the initial infection in order

for protective type 1 responses to develop, but once a popu-

lation of Th1 cells is established, IL-12 is not required for the

cells to mediate protection [244]. The dispensability of IL-12

after establishment of type 1 responses was strongly supported

by a study in which mature Th1 cells adoptively transferred

into severe combined immunodeficiency (SCID) mice were able

to protect the mice from Leishmania infection without addition

of recombinant IL-12 [245]. As Th1 cells do not actually secrete

IL-12 (IL-12 is secreted only by antigen-presenting cells), IL-

12 cannot have been necessary for the protective effect of the

Th1 cells against infection.

Although addition of cytokines or anti-cytokine antibodies

at the time of initial infection is able to reverse the type 1/type

2 polarity at the outset of the immune response, it has proved

difficult to reverse type 1 or type 2 responses in vivo once they

have already been established. Conversely, it has been possible

to reverse the phenotype of populations of ex vivo T cells taken

from animals with established infection [115, 246]. These stud-

ies raised an interesting question: if populations of ex vivo T

cells taken from mice with established infections can be reverted

in vitro, why can’t the phenotype of the overall immune re-

sponse be reversed in vivo? A likely answer was provided by

Nabors et al. [247]. These investigators administered IL-12 with

or without a chemotherapy agent to mice with Leishmania

infections. Only the combination of IL-12 and the antimicrobial

agent was able to reverse the established nonhealing type 2

response in vivo, allowing a healing type 1 response to develop.

The implication is that decreasing the antigenic burden of the

infected animals was crucial to disinhibiting the animals’ type

1 immunity.

In concordance with this finding, inoculation of low infec-

tious doses of Leishmania in Balb/C mice induced a type 1

response rather than the expected type 2 response [248, 249].

This is consistent with the notion that high infectious inocu-

lations stimulate type 2 immunity, whereas lower inoculations

allow protective type 1 inflammation to develop. These results

indicate that antimicrobial chemotherapy is a powerful tool for

inducing healing type 1 responses in hosts whose normal type

1 immunity is suppressed by overwhelming antigenic burden.

Bacterial infections. Pathogenic Escherichia coli and Sal-

monella typhimurium directly induced IFN-g in vivo in infected

mice. Strains of mice producing higher levels of IFN-g cleared

the microbes up to 10-fold more effectively, making them re-

sistant to infection [250], whereas IFN-g gene knockout mice

suffered from severe septicemia following oral inoculation

[251]. As well, ex vivo spleen cells taken from mice with acute

E. coli pyelonephritis produced IL-2 and IFN-g but no IL-4

during the first 7 days after infection [252]. Thereafter, a gradual

switch in profiles was noted, such that by several months after

infection the level of type 1 cytokines was decreased. This is

consistent with the notion that the immune system uses type

1 responses for protection against acute infection and switches

to type 2 responses when the danger is passed in order to

reestablish homeostasis and protect the host from autoinflam-

matory destruction.

Exogenous IL-12 induced long-lasting protective type 1 im-

munity in mice infected with Listeria monocytogenes [253, 254],

and IL-102/2 knockout mice were resistant to infection by Lis-

Dow




teria. Such knockout mice quickly developed more intensely

polarized type 1 responses than their wild-type littermates, so

that by 48–72 h after infection, their microbial tissue burden

was 50-fold lower than that of the wild-type mice [255]. An

elegant study compared early ex vivo gd T cell cytokines fol-

lowing murine infection by Listeria or the helminth Nippo-

strongylus. Within several days of infection, Listeria induced gd

T cells to secrete a type 1 profile of cytokines, whereas Nip-

postrongylus infection induced a rapid secretion of type 2 cy-

tokines [256]. This is consistent with in vitro data suggesting

that intracellular pathogens with innately antigenic fractions

induce early IL-12 release from leukocytes, whereas large ex-

tracellular pathogens induce frustrated phagocytosis, thereby

eliciting a type 2 response. Type 1 responses are also protective

against other bacteria, such as Pseudomonas, Yersinia, and Kleb-

siella [257–261].

Mycobacterial infections. Type 1 immunity has also been

shown to be protective against mycobacteria. Mice inherently

resistant to Mycobacterium leprae produced IL-12 early on at

the site of infection [262, 263], but mice susceptible to M.

leprae infection failed to produce early IL-12 [262]. When IL-

12 was administered to mice with established M. leprae infec-

tions, bacteria burdens were markedly decreased.

Orme et al. studied the evolution of an immune response

to tuberculosis in infected mice by pulsing ex vivo CD4 cells

with microbial fractions and measuring the resultant cytokines

released [264]. Early during infection, and peaking with the

time of maximum protective inflammation, IFN-g dominated

the cytokine response. By 3–5 weeks later, when the infection

had been contained and granulomas had begun to organize in

vivo, IL-4 and IL-10 dominated the cytokine profile, and IFN-

g was markedly suppressed. This is in concordance with the

recurrent theme that type 1 cytokines are expressed during the

protective phase of an immune response, and a switch is made

to expression of type 2 cytokines during the resolution phase.

Fungal infections. Findings in studies of the role of type

1/type 2 immunity in Candida, Coccidioides, Cryptococcus, and

Aspergillus infections parallel closely the findings from the

Leishmania model: mice susceptible to fungal infections mount

type 2 responses to the organisms, but resistant mice mount

type 1 responses [265–270]. Blocking IL-4 or IL-10 at the time

of infection of Balb/C mice with Candida increased the level

of IFN-g-induced cell-mediated immunity, which effectively

protected these normally susceptible mice from the fungus [89,

271]. Indeed, inhibition of IL-4 allowed 81% of mice to survive

the infection; none of the untreated control mice survived

[271].

Adding to the notion that high microbial burden suppresses

type 1 immunity, normally susceptible mice infected with sub-

lethal inocula of Candida developed type 1 immunity instead

of their usual type 2 immune response [272]. This reversal of

immunologic phenotype was due to diminished induction of

IL-4 secretion by the lower inoculum. Furthermore, lowering

fungal burden in infected mice by treatment with either am-

photericin B or fluconazole induced a healing type 1 immune

response, an effect potentiated by blockade of IL-4 [273, 274].

Therefore, it is the balance of IL-12 and IL-4 induced early

after infection that determines the eventual phenotype adopted

by the adaptive immune response. High microbial burden tips

the balance in favor of IL-4, suppressing cell-mediated im-

munity and polarizing the immune response toward a type 2

phenotype. Antimicrobial chemotherapy is an effective inter-

vention to favor type 1 immunity by lowering microbial burden.

Type 2 Protective Models

Helminths. The same tendency toward type 2 immune

responses that makes Balb/C mice inherently susceptible to

bacterial infections makes them inherently resistant to infection

by helminths [275]. In addition, strains of mice prone to type

1 responses, although innately resistant to most bacteria, are

inherently susceptible to helminthic infections [275]. Therefore,

unlike every disease model so far discussed, it is type 2 im-

munity rather than type 1 immunity that protects mammals

from helminths [275–277]. Type 2 responses correlate with

diminished worm burden, whereas type 1 responses allow

chronic infection and scarring to develop [278]. Mast cell ac-

tivation has been shown to be a key component of type 2

immunity to various helminths, including Trichinella and Nip-

postrongylus [279–281]. IL-9 is important in mast cell activa-

tion, which increases gastrointestinal peristalsis that successfully

expels parasites from the gut [282]. Indeed, transgenic mice

overexpressing IL-9 were highly resistant to trichinella infection

[283], and blockade of IL-9 worsened infection in mice nor-

mally resistant to trichuris infection [284].

Abrogation of IFN-g or administration of exogenous IL-4

in mice susceptible to helminths reversed their normal type 1

immunity, and the resultant type 2 response mediated expulsion

of the parasite from the gut [285]. Conversely, blocking IL-4

or administering IL-12 in normally resistant mice led to the

development of futile type 1 responses, which allowed chronic

infection to develop [285–287].

Although the above studies provide convincing evidence that

type 2 immunity is protective against helminths, recent revi-

sionist thinking has challenged this notion [288]. Although

conceding that type 2 immunity is the natural mammalian

response to helminths, the revisionist theory states that type 2

immunity occurs because helminths deviate the host immune

response to a nonprotective posture, enabling the worms to

successfully infect the host. The evidence in support of this

notion derives from studies in which serum IgE and IL-4 levels

have failed to correlate with host protection against helminths

[289–295]. In fact, IL-4 knockout mice are perfectly resistant

Dow




Figure 4. Immunity to Trichuris muris in IL-4 and IL-13 knockout (IL-42/2 and IL-132/2) mice. Left Y-axis, Ex vivo cytokine production by peripheralblood mononuclear cells; right Y-axis, tissue worm burden (number of worms cultured from cecum and colon). C57BL and 129 are the parent strainsof the IL-42/2 and IL-132/2 knockout mice, respectively (figure reproduced with permission from [297]).

to Nippostrongylus infection, indicating that IL-4 is not required

for protection against this helminth in mice [296].

The notion that type 2 immunity is a maladaptive response

to helminthic infection was directly challenged by an elegant

study by Bancroft et al. (figure 4) [297]. These investigators

compared immune responses in wild-type, IL-42/2, and IL-132/

2 knockout mice following infection with Trichuris muris. Wild-

type mice mounted strong type 2 responses that successfully

cleared the helminth. IL-4 knockout mice failed to mount type

2 responses; they produced no IL-4 and had markedly dimin-

ished IL-5 and IL-13 levels, which resulted in a huge increase

in worm burden. It is interesting that in contrast to IL-4 knock-

out mice, production of IL-4 and IL-5 by the IL-13 knockout

mice was only mildly diminished in comparison with that in

wild-type animals, indicating that they still mounted type 2

responses. Nevertheless, despite their apparent type 2 response,

the IL-13 knockout mice suffered from twice the worm burden

than that in the IL-4 knockout mice. Thus a type 2 immune

response is protective against Trichuris only if IL-13 is present.

IL-4 is a key inducer of type 2 immunity, but IL-13 can

mimic some of IL-4’s function by binding to a shared IL-4/IL-

13 receptor [298–300]. Furthermore, much like IL-12 induces

type 1 immunity but IFN-g actually mediates type 1 effects,

IL-13 appears to be more important than IL-4 for the actual

protective effect of type 2 immunity against helminths. Indeed,

whereas IL-4 knockout mice expel Nippostrongylus normally

from the gut, IL-13 knockout mice and IL-4/IL-13 double-

knockout mice are extremely susceptible to Nippostrongylus in-

fection [301, 302].

An overwhelming majority of data indicate that type 2 im-

munity is the key to mammalian protection against infection

by helminths. IL-4 is important for induction of type 2 im-

munity, but IL-5, IL-9, and IL-13 are the key effector cytokines

in type 2–mediated protection. IL-5 and IL-9 act via eosinophil

and mast cell stimulation. Although it has been suggested that

IL-13 acts via secondary induction of TNF [303], its definitive

mechanism remains obscure.

RELEVANT DISEASE MODELS: CLINICALDISEASES

Leishmania. The findings of studies of immunity in pa-

tients infected with Leishmania parallel the data generated in

animal models. mRNA analysis of cutaneous lesions caused by

Leishmania braziliensis demonstrated 2 profiles in human pa-

tients [304]. Biopsy specimens from patients with localized dis-

ease displayed prominent mRNA coding for IL-2, IFN-g, and

LT-a, consistent with a protective type 1 immune response.

Biopsies of lesions from patients suffering from destructive mu-

cocutaneous American leishmaniasis demonstrated a marked

increase in the level of IL-4 mRNA, which is consistent with a

failed type 2 host immune response.

Analogous to murine data on infectious burden, expression

of IL-10 was found to be higher in patients with active Leish-

mania donovani infections than in patients who had been cured

of disease [305]. T cells from patients who had recovered from

limited Leishmania infections expressed high levels of IFN-g

and LT-a, but little or no IL-4, when exposed in vitro to Leish-

mania antigens [306]. Conversely, ex vivo cytokine production

by lymphocytes taken from patients with severe visceral leish-

Dow




Figure 5. Change in cytokine pattern over time following BCG vaccination in humans. Ex vivo peripheral blood mononuclear cells (PBMCs) wereanalyzed by fluorescence-activated cell-sorting (FACS) for intracellular cytokine production on sequential days following administration of BCG vaccineto healthy volunteers. The percentage of mononuclear cells expressing type 1 cytokines (IL-2, IFN-g, lymphotoxin [LT]-a) is shown on the left y axis,and the percentage of cells expressing type 2 cytokines (IL-4, IL-5, IL-10) is shown on the right y axis (figure reproduced with permission from [328]).

maniasis was dominated by the type 2 cytokines IL-4 and IL-

10 [307]. Thus type 1 immunity is the key to protection against

Leishmania infections in humans, and a high infectious burden

suppresses the human immune system from mounting type 1

responses.

Bacterial infections. Direct examination of cytokine pro-

files of patients infected with Haemophilus influenza and Strep-

tococcus pyogenes revealed that IFN-g and LT-a were the dom-

inant cytokines elicited at the site of infection, and no IL-4 was

found [308]. Similarly, Lactobacillus, S. agalactiae, S. pyogenes,

and Listeria directly induced IL-12 and IFN-g but not IL-4

secretion from human leukocytes [309–311]. Case reports con-

cerning patients with identified genetic defects in cytokine or

cytokine receptor genes are illustrative of the role of cytokines

in host defense against infection. For example, patients with

defects in the IFN-g, IL-12, or IL-12-receptor genes are unable

to produce IL-12 and/or IFN-g and as a result have developed

severe infections caused by Salmonella [312, 313], Streptococcus,

or Listeria [314, 315].

Mycobacterial infections. The dichotomy between pa-

tients with lepromatous leprosy, which is the disseminated, se-

vere form of the disease, and those with tuberculoid leprosy,

which is local disease controlled by the immune system, par-

allels in vivo cytokine production [316]. Lepromatous leprosy

develops in patients who mount type 2 immune responses to

the organism, whereas tuberculoid leprosy is synonymous with

a successful type 1 immune response to M. leprae [164, 317].

Mononuclear cells from lepromatous leprosy patients secreted

high levels of prostaglandin E and IL-10, thereby suppressing

IL-12 induction of IFN-g, whereas cells from tuberculoid lep-

rosy patients did not secrete prostaglandin E and IL-10 [164].

Furthermore, lesion-biopsy specimens from patients with tu-

berculoid leprosy contained Th1 cells expressing 10-fold higher

levels of IL-12 mRNA than in lepromatous patients [316]. Con-

versely, biopsy specimens from lepromatous patients contained

high levels of IL-4 and IL-10.

There is also a dichotomy between a high humoral response

and a high DTH response among patients infected with My-

cobacterium tuberculosis [318, 319]. Patients with active tuber-

culosis have been shown to have diminished DTH reactions,

cell proliferation, and IFN-g production in response to PPD,

as well as higher levels of antimycobacterial antibodies, than

do PPD-positive, uninfected case control subjects [320]. In

addition, infected patients produced higher levels of IL-4 [321,

322]. These data are consistent with the notion that active M.

tuberculosis infection was related to dominant type 2 immunity,

whereas protected patients mounted type 1 immune responses

to the organism. Multiple published case reports of severe my-

cobacterial infections in patients with genetic IFN-g or IL-12

deficiencies confirm the importance of type 1 immunity in

protection against these organisms [312, 313, 315, 323–327].

As in mice, immunity to mycobacteria in humans evolves

over time (figure 5) [328]. Within 5 days after BCG vaccination,

leukocyte production of IL-2, IFN-g, and LT-a was shown to

increase dramatically, whereas production of Th2 cytokines re-

mained minimal. By a week after inoculation, the production

of Th1 cytokines reached a plateau and there was a sudden

burst in IL-4 production. By days 10–12 after vaccination, there

Dow




was a remarkable suppression of type 1 cytokine activity and

a rise in IL-5 and IL-10 production. This elegant study provided

powerful confirmatory evidence that type 1 immunity is directly

induced by mycobacteria and that the immune system naturally

switches over time to a type 2 immune response in order to

reestablish homeostasis after the battle is won.

Fungal infections. Similar to antigenic fractions from typ-

ical bacteria, certain Candida antigens directly induced secre-

tion of IL-2 and IFN-g, but not IL-4 and IL-10, from human

leukocytes [329]. It is interesting that patients with chronic

mucocutaneous candidiasis seem refractory to the normal in-

duction of IL-2 and IFN-g. Cells from such patients produced

an altered profile of cytokines, more reminiscent of a type 2

profile, when stimulated in vitro with Candida antigens [330].

Since IL-4 inhibits human phagocytes from killing Candida

[331], this switch to a type 2 profile can explain the inherent

susceptibility of such patients to candidal infections.

The importance of IFN-g and type 1 immunity in host de-

fense against fungal infections is made clear by observations of

patients with chronic granulomatous disease. Such patients suf-

fer from an inability to generate a respiratory burst in phag-

ocytic cells and therefore commonly develop invasive pyogenic

and fungal infections, often caused by Aspergillus [332]. Treat-

ment with recombinant IFN-g stimulates killing of fungi by

phagocytes of patients with chronic granulomatous disease

[333] and thereby reduces the frequency and severity of clin-

ically apparent fungal infections [334]. Therefore, IFN-g, and

by extension type 1 immunity, is protective against fungal

infections.

HIV. Numerous studies have found that during the pro-

gression of AIDS, mononuclear cells lose the ability to secrete

IL-2, IL-12, and IFN-g and produce increased levels of IL-4

and IL-10 [335–340]. Because of the loss of IL-2 secretion, T

cells from HIV-positive patients are typically unable to prolif-

erate when stimulated by common antigens. However, addition

of recombinant IL-12 to in vitro cultures of T cells restored

not only the lymphocytes’ ability to proliferate but also their

production of IL-2 and IFN-g [341]. Analyses of the impact

of highly active antiretroviral therapy on immune reconstitu-

tion in patients with AIDS have been recently published [342,

343]. Investigators reported that potent inhibition of viral rep-

lication reversed the suppression of IL-2 and IFN-g production

in the patients’ leukocytes while markedly diminishing their

overproduction of IL-4 and IL-10. This paralleled a recovery

in T cell counts. Similar results have been found in studies of

children treated with highly active antiretroviral therapy [344].

Therefore, clinicians may be able to reverse the immune dys-

regulation in patients with AIDS by affecting viral suppression.

Th1 cells express the chemokine receptor CCR5, whereas

Th2 cells express the CXCR4 receptor [345–347]. M-tropic

strains of HIV, which are the infectious particles, use CCR5 as

a co-receptor for viral entry into the host cell, whereas T-tropic

HIV strains, which emerge as the dominant strains during the

progression of AIDS, use CXCR4 [348, 349]. This switch in

receptor usage during disease progression parallels the fre-

quency with which Th1 and Th2 cells are found in vivo. Thus

part of the pathogenesis of AIDS is a selective loss of Th1 cells,

which then forces the virus to adapt to infect Th2 cells in order

to persist in the host.

Although suppression of IL-12 production by phagocytes is

one mechanism by which HIV acts to suppress type 1 im-

munity, in vivo studies have demonstrated an additional effect.

Hormonal abnormalities, such as a loss of serum testosterone

derivatives, are commonly seen in patients with AIDS and result

in lean-muscle-mass wasting [350–352]. In fact, decreases in

serum DHEA were linearly related to loss of CD4 cells during

AIDS progression [353, 354], and patients with serum DHEA

levels !180 ng/mL had a 2.3 RR for progression to AIDS within

2 years [355, 356]. Conversely, loss of CD4 cells and AIDS

progression were inversely correlated with serum cortisol levels

[350, 354, 357]. Therefore, AIDS is associated with hormonal

conditions—namely, low DHEA and high glucocorticoid lev-

els—which suppress IL-2, IFN-g, and IL-12 production and

stimulate IL-4 and IL-10 production [358]. This is the perfect

recipe for systemic suppression of type 1 responses and stim-

ulation of type 2 responses.

These studies provide the theoretical underpinning for the

hypothesis that HIV induces a gradual paralysis of type 1 im-

munity, allowing expansion of Th2 cells at the expense of naive

T cells and Th1 cells. This theory was confirmed by clinical

observations in several key studies. As IgE is a highly specific

bioassay for type 2 immune responses, Vigano et al. compared

serum levels of IgE in 58 vertically infected HIV-positive chil-

dren and 35 serorevertant control subjects (figure 6) [359, 360].

They found that HIV-positive children had significantly higher

levels of IgE antibody than did the serorevertants, and 75% of

the children whose IgE levels were abnormally high had a pre-

cipitous drop (by >30%) in their CD4 counts over the sub-

sequent year. Therefore, HIV-positive children suffer from dys-

regulated immunity in which type 2 responses overwhelm type

1 responses, and the rate of loss of type 1 immunity parallels

the loss of T helper cells.

HIV is unique among the disorders so far discussed in that

several interventional cytokine trials involving humans have

been performed. Kovacs et al., for example, published an im-

pressive randomized trial of IL-2 plus zidovudine versus zi-

dovudine alone in the treatment of 60 patients with AIDS [361].

After a year of follow-up, the CD4 cell counts of patients in

the IL-2 group doubled from a mean of 428 cells/mL to 916

cells/mL, whereas those of the patients treated with zidovudine

alone dropped from a mean of 406 cells/mL to 329 cells/mL.

There was no difference in the viral load between the 2 groups

Dow




Figure 6. Ex vivo cytokine production by peripheral blood mononuclear cells and serum IgE levels in 58 vertically infected children with HIV infectionor AIDS, compared to that in 35 serorevertant HIV-negative control subjects (figure reproduced with permission from [359, 360]).

at the end of the year. Thus the difference in T helper cell

counts at the end of the year was unrelated to the degree of

viral suppression. Rather, the exogenous IL-2 restored the im-

mune system’s ability to produce more peripheral T cells, a

finding confirmed by more recent clinical trials [362–364].

Smaller studies of subcutaneous IL-2 in HIV-infected pa-

tients by Davey et al. [365] and De Paoli et al. [366] yielded

similar results. The latter study examined the effect of IL-2 on

naive T cells, identified by staining for the surface marker

CD45RA. Like Kovacs et al. [361], De Paoli et al. [366] reported

a doubling of CD4 cell counts at 1 year in AIDS patients treated

with IL-2 and antiretrovirals and no significant change in the

CD4 counts of patients treated with antiretroviral therapy alone.

Like the total T cell population, the numbers of naive T cells

also doubled in the IL-2-treated patients, whereas there was no

change in the number of naive T helper cells in the group

treated with antiretrovirals alone. Therefore, IL-2 not only en-

ables activation of and expansion of the number of Th1 effector

cells but also promotes survival of naive Th0 cells in patients

with AIDS. In addition, Khatri et al. [367] studied ex vivo

cytokine production by T cells in patients with AIDS who were

treated with IL-2. They reported that the patients’ T cells pro-

duced twice as much IFN-g and half as much IL-10 during

the IL-2 therapy as they did before or after treatment.

The final proof of a shift from type 1 to type 2 immunity

in patients with AIDS derives from an elegant study by Norbiato

et al. [368]. These investigators studied 10 patients with AIDS

who developed Addisonian symptoms and were found to be

glucocorticoid-resistant, as determined by low-affinity binding

of their glucocorticoid receptors to dexamethasone. The glu-

cocorticoid-resistant AIDS patients were compared to 10 case-

control AIDS patients with normal steroid receptors and 10

HIV-negative control subjects. Glucocorticoid-resistant AIDS

patients had urinary cortisol levels 5 times higher than those

in the HIV-negative patients. However, because their resistance

to cortisol spared them from its immunosuppressive effects

[369], T cells from the glucocorticoid-resistant patients were

able to secrete high levels of IL-2 and maintain a normal ratio

of serum IFN-g to IL-4 (figure 7).

Conversely, although patients with AIDS who had normal

steroid receptors had urinary cortisol levels somewhat lower

than those of the steroid-resistant patients with AIDS, the cor-

tisol completely suppressed endogenous IL-2 production in

these patients (figure 7). This loss of IL-2 secretion almost

totally abrogated IFN-g production, whereas IL-4 and IL-10

production were strongly upregulated. A comparison of serum

IgE levels in the cortisol-resistant and normal-receptor patients

with AIDS closes the argument. The IgE levels of glucocorti-

coid-resistant patients with AIDS were barely elevated in com-

parison with those of HIV-negative control subjects, which in-

dicates an essentially normal ratio of in vivo type 1/type 2

immunity. Conversely, patients with AIDS with normal steroid

receptors had IgE levels 100-fold higher than those of HIV-

negative control subjects. Clearly, these patients with AIDS were

suffering from an overwhelming excess of type 2 immunity.

Thus in vitro and in vivo data indicate that HIV, beyond

simply killing T cells, disrupts normal homeostasis of type 1

and type 2 immunity. Abnormally high levels of glucocorticoids

and suppressed levels of DHEA, along with direct viral sup-

pression of IL-12 production, create a host environment that

suppresses differentiation of type 1 effector cells and stimulates

development of type 2 immune responses that are ineffective

at controlling a broad range of pathogens.

Dow




Figure 7. Twenty-four-hour urine cortisol, serum cytokine, and serum IgE levels in glucocorticoid-resistant patients with AIDS (AIDS-GR) andglucocorticoid-susceptible control patients with AIDS (AIDS-GS) and HIV-negative control subjects (HIV2; figure reproduced with permission from [368]).

RELEVANT DISEASE MODELS: TYPE 1/TYPE 2HOMEOSTASIS

As repeatedly discussed, the immune system restores ho-

meostasis by switching a type 1 response into a type 2 response

once an infection has been cleared. Recent data from Gett and

Hodgkin shed new light on the mechanism of this switch [370].

These investigators developed a sophisticated experimental sys-

tem to determine how many cell divisions a given T cell had

undergone after activation. They simultaneously measured in

vitro cytokine production by the lymphocytes, allowing cor-

relations to be drawn between cell division number and cy-

tokine production (figure 8).

Immediately after activation of naive T cells, only IL-2 was

produced. During the subsequent cell divisions, polarization

began to occur, and IFN-g was first secreted at cell division

number 4. IL-4 secretion began at division 6, accompanied by

the gradual waning of IL-2 secretion. IFN-g production reached

a plateau by cell division 7, at which time IL-4 production

began to logarithmically increase. Finally, at cell division 8, there

was a sharp burst in production of IL-10. Unfortunately, the

limit of the technology is about 8 cell divisions. However, with

a sudden upswing in IL-10 production at division 8, it can be

hypothesized that cell divisions occurring beyond 8 would be

associated with a loss of IFN-g secretion and the establishment

of a polarized Th2 profile of IL-4 and IL-10 secretion.

Thus there is a molecular genetic basis for the clinical phe-

nomenon of switching from a type 1 to a type 2 response over

time during infection. T cells appear to gradually lose the ability

to secrete pro-inflammatory cytokines as they mature after mul-

tiple cell divisions.

VACCINES AND IMMUNOTHERAPY: PARADOXAND PROMISE

Clinicians traditionally measure vaccine-induced protective

immunity by following antibody titers. Furthermore, passive

immunization, or administration of exogenous antibody, me-

diates protection against a variety of infections. Thus, although

the model outlined above indicates that type 1 responses are

the keys to protection against most infections, paradoxical ob-

servations suggest that vaccines and passive immunization rely

on type 2 immunity to mediate protection.

Three concepts resolve this paradox, fitting the mechanisms

of vaccines and passive immunization with the type 1/type 2

model. The first concept is that type 1 immunity does not

actively suppress antibody responses. Although titers are lower

in dominant type 1 responses than in type 2 responses, Th1

cells are quite capable of inducing antibody production by B

cells [13]. Thus antibody production is consistent with either

a type 1 or type 2 response, depending on the subtypes of

antibody present. The IFN-g produced by Th1 cells causes

antibody class switching from IgM to the IgG1 and IgG3 sub-

types, rather than the IgG2, IgG4, and IgE that are induced by

IL-4. IFN g–induced IgG1 and IgG3 bind avidly via their Fc

portions to the Fcg receptor of phagocytes. Thus, by serving

as opsonins, antibody induced during a type 1 immune re-

sponse synergistically increases the effectiveness of cell-medi-

ated immunity.

The second concept is that type 2 immunity, in addition to

inducing antibody, actively suppresses cell-mediated immunity.

Thus administration of exogenous antibody is not equivalent

to induction of a type 2 immune response. Rather, passive

Dow




Figure 8. Cytokine secretion as a function of T cell division. In vitro–activated murine T lymphocytes were stained with an intracellular fluorescentdye whose intensity decreases with each cell division. FACS was used to sort lymphocytes into populations of equivalent cell-division number. Thecultures were restimulated with anti-CD3 antibody, and cytokines in the supernatants were analyzed by ELISA, allowing cytokine production to bematched to T cell division number (figure reproduced with permission from [370]).

immunization with exogenous antibody garners the immu-

nologic benefit of a humoral response without the added deficit

of suppressing cell-mediated immunity. Instead, passive im-

munization synergizes with type 1 immunity by providing extra

opsonins to assist activated phagocytes. Passive immunization

therefore does not fit into either the type 1 or type 2 description

of endogenous immunity. This is logical, since passive im-

munization is obviously not a normal, physiological component

of mammalian immune systems.

Although antibody titers are used clinically to determine the

efficacy of vaccines, this correlation of high titers with protective

immunity cannot be reliably interpreted as an indication that

vaccines work via induction of type 2 immunity. Although there

is an inverse relationship between the degree of cell-mediated

and humoral immunity elicited by a given antigen, the ratio

of type 1/type 2 immunity can range from highly polarized to

equivalent (figure 1). Indeed, Parish demonstrated 2 zones of

humoral and cell-mediated equivalency in his seminal article

[3]. Thus the third concept is that since most experimental

studies of vaccines examine only the humoral response, and

clinically there are no useful cell-mediated immune assays, the

correlation of high antibody titers with protective immunity

cannot be interpreted in terms of the type 1/type 2 paradigm.

There is no way to know to what degree, on the scale dem-

onstrated by Parish [3], a given vaccine tilts the balance of type

1/type 2 immune response in a patient. High antibody titers

might reflect a state of type 1/type 2 equivalency, or they might

reflect stimulation of antibody by Th1 cells rather than Th2

cells. Indeed, antibody induced by vaccines may be of the IgG1

or IgG3 isotype, consistent with a type 1 immune profile [371].

Only after directly analyzing cytokine patterns elicited by

vaccines or concurrently studying humoral and cell-mediated

responses can one comment on the relative effects of a vaccine

on inducing type 1/type 2 immunity. When such studies have

been undertaken, a dominance of type 1 immunity has been

found to be elicited by vaccines [371, 372].

Type 1 outcomes generate both cell-mediated and humoral

responses that act synergistically, whereas type 2 outcomes gen-

erate humoral responses but actively suppress cell-mediated

responses. Thus the type 1/type 2 immunity model indicates

that vaccines intended for virtually all infections, save those

directed at large, nonphagocytosable eukaryotes, should be de-

signed to skew the induced response toward a type 1 profile.

Multiple mechanisms to mediate vaccine-induced type 1 po-

larization have been described, including the use of IFN-g and

IL-12 as vaccine adjuvants [373–376] and the inclusion of genes

coding for IFN-g, IL-12, or CpG motifs in DNA vaccines

[377–381]. In animal models, vaccines inducing type 1 im-

munity have been proven highly effective at preventing infec-

tions, whereas vaccines inducing type 2 immunity increase sus-

ceptibility to infection [270, 373, 374, 380, 382–386].

CONCLUSIONS: A UNIFYING HYPOTHESIS

Type 1 immunity is the default response to all infections by

normal inocula of intracellular or phagocytosable microbes oc-

Dow




curring in nonimmunosuppressed hosts. Type 1 immune re-

sponses clear such pathogens, thereby diminishing further an-

tigenic stimulation for type 1 immunity. In addition, T

lymphocytes naturally switch from production of type 1 cy-

tokines to production of type 2 cytokines as they progress

through multiple cell divisions. Therefore, over time a type 1

immune response will tend to convert into a type 2 response,

allowing homeostasis to be reestablished. However, with per-

sistent antigenic stimulation—for example, if the type 1 im-

mune response is never able to completely clear the infec-

tion—continual stimulation of T cells can induce chronic type

1 responses, leading to host tissue destruction.

Conversely, type 2 immunity is the default response to in-

fections by large, extracellular pathogens that cannot be phag-

ocytosed, such as helminths. Type 2 immunity naturally de-

velops over time from type 1 immune responses. However, in

patients who have excess sympathetic stimulation before in-

fection, have excess glucocorticoids or high estrogen or pro-

gestin levels, are IL-2-deficient because of cyclosporine or FK-

506, or are inoculated by an overwhelming microbial burden,

the usual type 1 response is suppressed and a type 2 response

occurs instead.

Clinical factors that induce glucocorticoid or sympathetic

responses will tend to make patients susceptible to infections

that would normally be dealt with by type 1 immune responses.

Malnutrition has been shown to suppress serum DHEA levels

and directly induce high systemic levels of glucocorticoids and

catecholamines [387–390], as has the presence of malignancy,

even independently of malnutrition [391]. Indeed, patients with

malignancies are prone to type 2 immunity at the expense of

type 1 responses [392, 393]. Furthermore, the clinical condi-

tions of congestive heart failure [394–396], chronic obstructive

pulmonary disease [397], and hepatic cirrhosis [398] are all

associated with hypersympathetic stimulation and high circu-

lating catecholamine levels, conditions suppressive to type 1

immunity. Finally, severe systemic stresses induced by traumatic

injury [399, 400], extensive surgery [401, 402], and the use of

total parenteral nutrition [403] have been shown to suppress

type 1 immunity and favor type 2 immunity.

The implications for clinicians from these data are three.

First, the paradigm of type 1 and type 2 immunity provides a

pathophysiological explanation for why patients with the above

systemic ailments are prone to severe infections. Second, the

model suggests new potential weapons in the clinical battle for

host defense. For example, the utilization of b-blockers to re-

verse catecholamine-induced suppression in patients such as

those with AIDS, trauma, congestive heart failure, or cirrhosis

or those in intensive care units is intriguing. We are unaware

of any published study reports describing the incidence of in-

fections in patients receiving b-2 agonist bronchodilators, cat-

echolamine pressors, or b-blockers for heart failure or hyper-

tension. Such data would be invaluable in the study of host

immunity to infection and could easily be obtained by careful

reporting of the incidence of infections in future clinical trials

of b-2 agonists, pressors, or b-blockers. Third, the model ex-

plains an important and previously unknown effect of anti-

microbial chemotherapy: lowering antigenic burden by treating

with antibiotics disinhibits protective type 1 immunity.

Reports have already been published of phase I/II clinical

trials utilizing several different type 1/type 2 cytokines to po-

larize patients’ immune responses toward appropriate pheno-

types. Early studies on the use of IL-2 and IL-12 in humans

revealed their potential for severe systemic adverse effects [404,

405]. Despite the initial setbacks in patients with cancer, the

use of newer schedules of dosing of IL-2 and IL-12 have dem-

onstrated impressive effects in patients with infectious diseases.

The use of low-dose adjuvant IL-2 in patients with multidrug-

resistant tuberculosis led to a 60% cure rate in these difficult-

to-treat patients [406], and the benefits of IL-2 for patients

with AIDS have already been described.

In addition, IL-12 has demonstrated antiviral effects with

minimal toxicity in patients with chronic hepatitis [407, 408].

Conversely, the anti-inflammatory effects of IL-10 in humans

[409–411] have led to its use in hyperinflammatory states rang-

ing from psoriasis [412] to organ transplantation immunosup-

pression [413] to Crohn’s disease [414], with promising results.

Blockade of cytokine effects has also been attempted. Specifi-

cally, inhaled recombinant IL-4 receptor has shown promise as

an anti-asthmatic agent, serving to soak up IL-4 in the airways

[415]. Finally, as mentioned earlier, the targeted design of small

molecules capable of disrupting or inducing transcription fac-

tors regulating Th1/Th2 polarization may provide an additional

set of clinical weapons to intervene in pathological states re-

sulting from aberrant type 1 or type 2 immunity.

However, exogenous administration of cytokines is a sys-

temic intervention, whereas the immune system normally reg-

ulates itself on the basis of the cytokine milieu present at local

microenvironments. Clinicians must develop techniques to ad-

minister cytokines in a localized fashion rather than flooding

the vascular compartment with them. Such techniques might

include the inclusion of genes coding for IL-12 or CpG motifs

in DNA vaccines against microbes and the use of liposomally

coated cytokines targeted toward in vivo–activated leukocytes

[416, 417].

Acknowledgments

We acknowledge Drs. Scott Filler and Michael Yeaman for

their invaluable suggestions and insightful input.

References

1. Metchnikoff E. Immunity in infective diseases. Binnie, FG, trans.Cambridge: Cambridge University Press, 1905. Reprint: The sourcesof science, no. 61. New York: Johnson Reprint Corporation, 1968.

Dow




2. Ehrlich P. Collected studies in immunity. New York: John Wiley &Sons, 1905.

2a. Coombs R, Gell P. The classification of allergic reactions underlyingdisease. In: Gell P, Coombs R, eds. Clinical aspects of Immunology.Oxford: Blackwell Scientific Publications, 1963:317–37.

3. Parish CR. Immune response to chemically modified flagellin. II.Evidence for a fundamental relationship between humoral and cell-mediated immunity. J Exp Med 1971; 134:21–47.

4. Parish CR, Liew FY. Immune response to chemically modified fla-gellin. III. Enhanced cell-mediated immunity during high and lowzone antibody tolerance to flagellin. J Exp Med 1972; 135:298–311.

5. Parish CR. Immune response to chemically modified flagellin. IV.Further studies on the relationship between humoral and cell-me-diated immunity. Cell Immunol 1973; 6:66–79.

6. Sercarz E, Coonz AH. Specific inhibition of antibody formation dur-ing immunological paralysis and unresponsiveness. Nature 1959; 184:1080–2.

7. Dresser DW. Specific inhibition of antibody production. Immunol1962; 5:161–8.

8. Dresser DW. Specific inhibition of antibody production. II. Paralysisinduced in adult mice by small quantities of protein antigen. Immunol1962; 5:378–88.

9. Mitchison NA. Induction of immunological paralysis in two zones ofdosage. Proc Roy Soc B 1964; 161:275–92.

10. Hahn H, Kaufmann SH, Miller TE, et al. Peritoneal exudate T lym-phocytes with specificity to sheep red blood cells. I. Production andcharacterization as to function and phenotype. Immunology 1979;36:691–8.

11. Hahn H, Kaufmann SH, Falkenberg F, et al. Peritoneal exudate Tlymphocytes with specificity to sheep red blood cells. II. Inflammatoryhelper T cells and effector T cells in mice with delayed-type hyper-sensitivity and in suppressed mice. Immunology 1979; 38:51–5.

12. Liew FY, Dhaliwal SS, Teh KL. Dissociative effects of malarial infectionon humoral and cell-mediated immunity in mice. Immunology1979; 37:35–44.

13. Mosmann TR, Cherwinski H, Bond MW, et al. Two types of murinehelper T cell clone. I. Definition according to profiles of lymphokineactivities and secreted proteins. J Immunol 1986; 136:2348–57.

14. Cher DJ, Mosmann TR. Two types of murine helper T cell clone. II.Delayed-type hypersensitivity is mediated by TH1 clones. J Immunol1987; 138:3688–94.

15. Umetsu DT, Jabara HH, DeKruyff RH, et al. Functional heterogeneityamong human inducer T cell clones. J Immunol 1988; 140:4211–6.

16. Rotteveel FT, Kokkelink I, van Lier RA, et al. Clonal analysis of func-tionally distinct human CD41 T cell subsets. J Exp Med 1988; 168:1659–73.

17. Rocken M, Muller KM, Saurat JH, et al. Lectin-mediated inductionof IL-4-producing CD41 T cells. J Immunol 1991; 146:577–84.

18. Sad S, Mosmann TR. Single IL-2-secreting precursor CD4 T cell candevelop into either Th1 or Th2 cytokine secretion phenotype. J Im-munol 1994; 153:3514–22.

19. Seder RA, Paul WE. Acquisition of lymphokine-producing phenotypeby CD41 T cells. Annu Rev Immunol 1994; 12:635–73.

20. Del Prete G, Maggi E, Romagnani S. Human Th1 and Th2 cells:functional properties, mechanisms of regulation, and role in disease.Lab Invest 1994; 70:299–306.

21. Ladel CH, Blum C, Dreher A, et al. Lethal tuberculosis in interleukin-6-deficient mutant mice. Infect Immun 1997; 65:4843–9.

22. Yamamoto M, Yoshizaki K, Kishimoto T, et al. IL-6 is required forthe development of Th1 cell–mediated murine colitis. J Immunol2000; 164:4878–82.

23. Yssel H, De Waal Malefyt R, Roncarolo MG, et al. IL-10 is producedby subsets of human CD41 T cell clones and peripheral blood T cells.J Immunol 1992; 149:2378–84.

24. de Waal Malefyt R, Abrams JS, Zurawski SM, et al. Differential reg-ulation of IL-13 and IL-4 production by human CD81 and CD41

Th0, Th1 and Th2 T cell clones and EBV-transformed B cells. IntImmunol 1995; 7:1405–16.

25. Groux H, Powrie F. Regulatory T cells and inflammatory bowel dis-ease. Immunol Today 1999; 20:442–5.

26. Moller G. Do suppressor T cells exist? Scand J Immunol 1988; 27:247–50.

27. Green DR, Webb DR. Saying the “S” word in public. Immunol Today1993; 14:523–5.

28. Seddon B, Mason D. The third function of the thymus. ImmunolToday 2000; 21:95–9.

29. Gottlieb MS, Schroff R, Schanker HM, et al. Pneumocystis cariniipneumonia and mucosal candidiasis in previously healthy homosexualmen: evidence of a new acquired cellular immunodeficiency. N EnglJ Med 1981; 305:1425–31.

30. Kariv I, Hardy RR, Hayakawa K. Two distinct non–T helper type 2interleukin-41 cell subsets in mice as revealed by single-cell cytokineanalysis. Eur J Immunol 1994; 24:549–57.

31. Miner KT, Croft M. Generation, persistence, and modulation of Th0effector cells: role of autocrine IL-4 and IFN-gamma. J Immunol1998; 160:5280–7.

32. Firestein GS, Roeder WD, Laxer JA, et al. A new murine CD41 Tcell subset with an unrestricted cytokine profile. J Immunol 1989;143:518–25.

33. Street NE, Schumacher JH, Fong TA, et al. Heterogeneity of mousehelper T cells: evidence from bulk cultures and limiting dilution clon-ing for precursors of Th1 and Th2 cells. J Immunol 1990; 144:1629–39.

34. Chen Y, Kuchroo VK, Inobe J, et al. Regulatory T cell clones inducedby oral tolerance: suppression of autoimmune encephalomyelitis. Sci-ence 1994; 265:1237–40.

35. Fukaura H, Kent SC, Pietrusewicz MJ, et al. Induction of circulatingmyelin basic protein and proteolipid protein-specific transforminggrowth factor–b1–secreting Th3 T cells by oral administration of my-elin in multiple sclerosis patients. J Clin Invest 1996; 98:70–7.

36. Powrie F, Carlino J, Leach MW, et al. A critical role for transforminggrowth factor–b but not interleukin 4 in the suppression of T helpertype 1–mediated colitis by CD45RB (low) CD41 T cells. J Exp Med1996; 183:2669–74.

37. Hafler DA, Kent SC, Pietrusewicz MJ, et al. Oral administration ofmyelin induces antigen-specific TGF-b1 secreting T cells in patientswith multiple sclerosis. Ann NY Acad Sci 1997; 835:120–31.

38. Groux H, O’Garra A, Bigler M, et al. A CD41 T-cell subset inhibitsantigen-specific T-cell responses and prevents colitis. Nature 1997;389:737–42.

39. Buer J, Lanoue A, Franzke A, et al. Interleukin 10 secretion andimpaired effector function of major histocompatibility complex classII–restricted T cells anergized in vivo. J Exp Med 1998; 187:177–83.

40. Szulc B, Piasecki E. Effects of interferons, interferon inducers andgrowth factors on phagocytosis measured by quantitative determi-nation of synthetic compound ingested by mouse bone mar-row–derived macrophages. Archivum Immunologiae et Therapiae Ex-perimentalis 1988; 36:537–45.

41. Livingston DH, Appel SH, Sonnenfeld G, et al. The effect of tumornecrosis factor–alpha and interferon-gamma on neutrophil function.J Surg Res 1989; 46:322–6.

42. Johnston RB Jr, Kitagawa S. Molecular basis for the enhanced res-piratory burst of activated macrophages. Fed Proc 1985; 44:2927–32.

43. Newburger PE, Ezekowitz RA, Whitney C, et al. Induction of phag-ocyte cytochrome b heavy chain gene expression by interferon gamma.Proc Natl Acad Sci USA 1988; 85:5215–9.

44. Diamond RD, Lyman CA, Wysong DR. Disparate effects of interferon-gamma and tumor necrosis factor–alpha on early neutrophil respi-ratory burst and fungicidal responses to Candida albicans hyphae invitro. J Clin Invest 1991; 87:711–20.

45. Dellacasagrande J, Capo C, Raoult D, et al. IFN-gamma-mediatedcontrol of Coxiella burnetii survival in monocytes: the role of cellapoptosis and TNF. J Immunol 1999; 162:2259–65.

46. Marodi L, Kaposzta R, Nemes E. Survival of group B streptococcus

Dow




type III in mononuclear phagocytes: differential regulation of bacterialkilling in cord macrophages by human recombinant gamma inter-feron and granulocyte-macrophage colony-stimulating factor. InfectImmun 2000; 68:2167–70.

47. Lapierre LA, Fiers W, Pober JS. Three distinct classes of regulatorycytokines control endothelial cell MHC antigen expression: interac-tions with immune g-interferon differentiate the effects of tumornecrosis factor and lymphotoxin from those of leukocyte a and fi-broblast b-interferons. J Exp Med 1988; 167:794–804.

48. Johnson DR, Pober JS. Tumor necrosis factor and immune interferonsynergistically increase transcription of HLA class I heavy- and light-chain genes in vascular endothelium. Proc Natl Acad Sci USA 1990;87:5183–7.

49. Volk HD, Gruner S, Falck P, et al. The influence of interferon-gammaand various phagocytic stimuli on the expression of MHC-class IIantigens on human monocytes: relation to the generation of reactiveoxygen intermediates. Immunol Lett 1986; 13:209–14.

50. Male DK, Pryce G, Hughes CC. Antigen presentation in brain: MHCinduction on brain endothelium and astrocytes compared. Immu-nology 1987; 60:453–9.

51. Goebeler M, Yoshimura T, Toksoy A, et al. The chemokine repertoireof human dermal microvascular endothelial cells and its regulationby inflammatory cytokines. J Invest Dermatol 1997; 108:445–51.

52. Teunissen MB, Koomen CW, de Waal Malefyt R, et al. Interleukin-17 and interferon-gamma synergize in the enhancement of proin-flammatory cytokine production by human keratinocytes. J InvestDermatol 1998; 111:645–9.

53. Rathanaswami P, Hachicha M, Sadick M, et al. Expression of thecytokine RANTES in human rheumatoid synovial fibroblasts. Differ-ential regulation of RANTES and interleukin-8 genes by inflammatorycytokines. J Biol Chem 1993; 268:5834–9.

54. Teran LM, Mochizuki M, Bartels J, et al. Th1- and Th2-type cytokinesregulate the expression and production of eotaxin and RANTES byhuman lung fibroblasts. Am J Respir Cell Mol Biol 1999; 20:777–86.

55. Nickoloff BJ, Naidu Y. Perturbation of epidermal barrier functioncorrelates with initiation of cytokine cascade in human skin. J AmAcad Dermatol 1994; 30:535–46.

56. Lundgren M, Persson U, Larsson P, et al. Interleukin 4 induces syn-thesis of IgE and IgG4 in human B cells. Eur J Immunol 1989; 19:1311–5.

57. Punnonen J, de Vries JE. IL-13 induces proliferation, Ig isotype switch-ing, and Ig synthesis by immature human fetal B cells. J Immunol1994; 152:1094–102.

58. Lai YH, Mosmann TR. Mouse IL-13 enhances antibody productionin vivo and acts directly on B cells in vitro to increase survival andhence antibody production. J Immunol 1999; 162:78–87.

59. Kuhn R, Rajewsky K, Muller W. Generation and analysis of interleu-kin-4 deficient mice. Science 1991; 254:707–10.

60. Snapper CM, Pecanha LM, Levine AD, et al. IgE class switching iscritically dependent upon the nature of the B cell activator, in additionto the presence of IL-4. J Immunol 1991; 147:1163–70.

61. Punnonen J, Aversa G, Cocks BG, et al. Interleukin 13 induces in-terleukin 4–independent IgG4 and IgE synthesis and CD23 expressionby human B cells. Proc Natl Acad Sci USA 1993; 90:3730–4.

62. Parsons JC, Coffman RL, Grieve RB. Antibody to interleukin 5 pre-vents blood and tissue eosinophilia but not liver trapping in murinelarval toxocariasis. Parasite Immunol 1993; 15:501–8.

63. Satoh T, Sun L, Li MS, et al. Interleukin-5 mRNA levels in blood andbone marrow mononuclear cells from patients with the idiopathichypereosinophilic syndrome. Immunology 1994; 83:308–12.

64. Simon HU, Plotz SG, Dummer R, et al. Abnormal clones of T cellsproducing interleukin-5 in idiopathic eosinophilia. N Engl J Med1999; 341:1112–20.

65. Warringa RA, Schweizer RC, Maikoe T, et al. Modulation of eosinophilchemotaxis by interleukin-5. Am J Respir Cell Mol Biol 1992; 7:631–6.

66. Ohnishi T, Sur S, Collins DS, et al. Eosinophil survival activity iden-tified as interleukin-5 is associated with eosinophil recruitment and

degranulation and lung injury twenty-four hours after segmental an-tigen lung challenge. J Allergy Clin Immunol 1993; 92:607–15.

67. Sarmiento EU, Espiritu BR, Gleich GJ, et al. IL-3, IL-5, and granu-locyte-macrophage colony-stimulating factor potentiate basophil me-diator release stimulated by eosinophil granule major basic protein.J Immunol 1995; 155:2211–21.

68. Lie WJ, Mul FP, Roos D, et al. Degranulation of human basophils bypicomolar concentrations of IL-3, IL-5, or granulocyte-macrophagecolony-stimulating factor. J Allergy Clin Immunol 1998; 101:683–90.

69. Renauld JC, Kermouni A, Vink A, et al. Interleukin-9 and its receptor:involvement in mast cell differentiation and T cell oncogenesis. JLeukoc Biol 1995; 57:353–60.

70. Godfraind C, Louahed J, Faulkner H, et al. Intraepithelial infiltrationby mast cells with both connective tissue–type and mucosal-type char-acteristics in gut, trachea, and kidneys of IL-9 transgenic mice. JImmunol 1998; 160:3989–96.

71. Robinson D, Hamid Q, Bentley A, et al. Activation of CD41 T cells,increased TH2-type cytokine mRNA expression, and eosinophil re-cruitment in bronchoalveolar lavage after allergen inhalation challengein patients with atopic asthma. J Allergy Clin Immunol 1993; 92:313–24.

72. Lukacs NW, Strieter RM, Chensue SW, et al. Interleukin-4–dependentpulmonary eosinophil infiltration in a murine model of asthma. AmJ Respir Cell Mol Biol 1994; 10:526–32.

73. Nicolaides NC, Holroyd KJ, Ewart SL, et al. Interleukin 9: a candidategene for asthma. Proc Natl Acad Sci USA 1997; 94:13175–80.

74. Kawashima T, Noguchi E, Arinami T, et al. Linkage and associationof an interleukin 4 gene polymorphism with atopic dermatitis inJapanese families. J Med Genet 1998; 35:502–4.

75. Temann UA, Geba GP, Rankin JA, et al. Expression of interleukin 9in the lungs of transgenic mice causes airway inflammation, mast cellhyperplasia, and bronchial hyperresponsiveness. J Exp Med 1998; 188:1307–20.

76. Shi HZ, Deng JM, Xu H, et al. Effect of inhaled interleukin-4 onairway hyperreactivity in asthmatics. Am J Respir Crit Care Med1998; 157:1818–21.

77. Shi HZ, Li CQ, Qin SM, et al. Effect of inhaled interleukin-5 onnumber and activity of eosinophils in circulation from asthmatics.Clin Immunol 1999; 91:163–9.

78. Li L, Xia Y, Nguyen A, et al. Effects of Th2 cytokines on chemokineexpression in the lung: IL-13 potently induces eotaxin expression byairway epithelial cells. J Immunol 1999; 162:2477–87.

79. Gajewski TF, Goldwasser E, Fitch FW. Anti-proliferative effect of IFN-gamma in immune regulation. II. IFN-gamma inhibits the prolifer-ation of murine bone marrow cells stimulated with IL-3, IL-4, orgranulocyte-macrophage colony-stimulating factor. J Immunol1988; 141:2635–42.

80. Gajewski TF, Fitch FW. Anti-proliferative effect of IFN-gamma inimmune regulation. I. IFN-gamma inhibits the proliferation of Th2but not Th1 murine helper T lymphocyte clones. J Immunol 1988;140:4245–52.

81. Demeure CE, Wu CY, Shu U, et al. In vitro maturation of humanneonatal CD4 T lymphocytes. II. Cytokines present at priming mod-ulate the development of lymphokine production. J Immunol1994; 152:4775–82.

82. D’Andrea A, Aste-Amezaga M, Valiante NM, et al. Interleukin 10 (IL-10) inhibits human lymphocyte interferon gamma production by sup-pressing natural killer cell stimulatory factor/IL-12 synthesis in ac-cessory cells. J Exp Med 1993; 178:1041–8.

83. Ohmori Y, Hamilton TA. IL-4-induced STAT6 suppresses IFN-gamma-stimulated STAT1-dependent transcription in mouse mac-rophages. J Immunol 1997; 159:5474–82.

84. Ito S, Ansari P, Sakatsume M, et al. Interleukin-10 inhibits expressionof both interferon alpha- and interferon gamma– induced genes bysuppressing tyrosine phosphorylation of STAT1. Blood 1999; 93:1456–63.

85. Rennick D, Davidson N, Berg D. Interleukin-10 gene knock-out mice:

Dow




a model of chronic inflammation. Clin Immunol Immunopathol1995; 76:S174–8.

86. Fiorentino DF, Zlotnik A, Vieira P, et al. IL-10 acts on the antigen-presenting cell to inhibit cytokine production by Th1 cells. J Immunol1991; 146:3444–51.

87. Cassatella MA, Meda L, Bonora S, et al. Interleukin 10 (IL-10) inhibitsthe release of proinflammatory cytokines from human polymorpho-nuclear leukocytes: evidence for an autocrine role of tumor necrosisfactor and IL-1 b in mediating the production of IL-8 triggered bylipopolysaccharide. J Exp Med 1993; 178:2207–11.

88. Laichalk LL, Danforth JM, Standiford TJ. Interleukin-10 inhibits neu-trophil phagocytic and bactericidal activity. Fems Immunol Med Mi-crobiol 1996; 15:181–7.

89. Romani L, Puccetti P, Mencacci A, et al. Neutralization of IL-10 up-regulates nitric oxide production and protects susceptible mice fromchallenge with Candida albicans. J Immunol 1994; 152:3514–21.

90. Kuga S, Otsuka T, Niiro H, et al. Suppression of superoxide anionproduction by interleukin-10 is accompanied by a downregulation ofthe genes for subunit proteins of NADPH oxidase. Exp Hematol1996; 24:151–7.

91. Oswald IP, Gazzinelli RT, Sher A, et al. IL-10 synergizes with IL-4and transforming growth factor-b to inhibit macrophage cytotoxicactivity. J Immunol 1992; 148:3578–82.

92. Cenci E, Romani L, Mencacci A, et al. Interleukin-4 and interleukin-10 inhibit nitric oxide–dependent macrophage killing of Candida al-bicans. Eur J Immunol 1993; 23:1034–8.

93. de Waal Malefyt R, Haanen J, Spits H, et al. Interleukin 10 (IL-10)and viral IL-10 strongly reduce antigen-specific human T cell prolif-eration by diminishing the antigen-presenting capacity of monocytesvia downregulation of class II major histocompatibility complex ex-pression. J Exp Med 1991; 174:915–24.

94. Enk AH, Angeloni VL, Udey MC, et al. Inhibition of Langerhans cellantigen-presenting function by IL-10: a role for IL-10 in inductionof tolerance. J Immunol 1993; 151:2390–8.

95. Groux H, Bigler M, de Vries JE, et al. Interleukin-10 induces a long-term antigen-specific anergic state in human CD41 T cells. J Exp Med1996; 184:19–29.

96. de Waal Malefyt R, Figdor CG, Huijbens R, et al. Effects of IL-13 onphenotype, cytokine production, and cytotoxic function of humanmonocytes: comparison with IL-4 and modulation by IFN-gamma orIL-10. J Immunol 1993; 151:6370–81.

97. Morris SC, Gause WC, Finkelman FD. IL-4 suppression of in vivo Tcell activation and antibody production. J Immunol 2000; 164:1734–40.

98. Kurt-Jones EA, Hamberg S, Ohara J, et al. Heterogeneity of helper/inducer T lymphocytes. I. Lymphokine production and lymphokineresponsiveness. J Exp Med 1987; 166:1774–87.

99. Fernandez-Botran R, Sanders VM, Oliver KG, et al. Interleukin 4 me-diates autocrine growth of helper T cells after antigenic stimulation.Proc Natl Acad Sci USA 1986; 83:9689–93.

100. Lichtman AH, Chin J, Schmidt JA, et al. Role of interleukin 1 in theactivation of T lymphocytes. Proc Natl Acad Sci USA 1988; 85:9699–703.

101. Chang TL, Shea CM, Urioste S, et al. Heterogeneity of helper/inducerT lymphocytes. III. Responses of IL-2- and IL-4-producing (Th1 andTh2) clones to antigens presented by different accessory cells. J Im-munol 1990; 145:2803–8.

102. Constant SL, Bottomly K. Induction of Th1 and Th2 CD41 T cellresponses: the alternative approaches. Annu Rev Immunol 1997; 15:297–322.

103. Seder RA, Gazzinelli R, Sher A, et al. Interleukin 12 acts directly onCD41 T cells to enhance priming for interferon gamma productionand diminishes interleukin 4 inhibition of such priming. Proc NatlAcad Sci USA 1993; 90:10188–92.

104. Hsieh CS, Macatonia SE, Tripp CS, et al. Development of TH1 CD41

T cells through IL-12 produced by Listeria-induced macrophages.Science 1993; 260:547–9.

105. Manetti R, Parronchi P, Giudizi MG, et al. Natural killer cell stim-ulatory factor (interleukin 12 [IL-12]) induces T helper type 1(Th1)–specific immune responses and inhibits the development ofIL-4-producing Th cells. J Exp Med 1993; 177:1199–204.

106. Wu CY, Demeure C, Kiniwa M, et al. IL-12 induces the productionof IFN-gamma by neonatal human CD4 T cells. J Immunol 1993;151:1938–49.

107. Swain SL, McKenzie DT, Weinberg AD, et al. Characterization of Thelper 1 and 2 cell subsets in normal mice. Helper T cells responsiblefor IL-4 and IL-5 production are present as precursors that requirepriming before they develop into lymphokine-secreting cells. J Im-munol 1988; 141:3445–55.

108. Betz M, Fox BS. Regulation and development of cytochrome c–specificIL-4-producing T cells. J Immunol 1990; 145:1046–52.

109. Kopf M, Le Gros G, Bachmann M, et al. Disruption of the murineIL-4 gene blocks Th2 cytokine responses. Nature 1993; 362:245–8.

110. Sornasse T, Larenas PV, Davis KA, et al. Differentiation and stabilityof T helper 1 and 2 cells derived from naive human neonatal CD41

T cells, analyzed at the single-cell level. J Exp Med 1996; 184:473–83.111. Nakamura T, Kamogawa Y, Bottomly K, et al. Polarization of IL-4–

and IFN-gamma–producing CD41 T cells following activation of naiveCD41 T cells. J Immunol 1997; 158:1085–94.

112. Doyle AG, Buttigieg K, Groves P, et al. The activated type 1–polarizedCD8(1) T cell population isolated from an effector site contains cellswith flexible cytokine profiles. J Exp Med 1999; 190:1081–92.

113. Perez VL, Lederer JA, Lichtman AH, et al. Stability of Th1 and Th2populations. Int Immunol 1995; 7:869–75.

114. Murphy E, Shibuya K, Hosken N, et al. Reversibility of T helper 1and 2 populations is lost after long-term stimulation. J Exp Med1996; 183:901–13.

115. Mocci S, Coffman RL. Induction of a Th2 population from a polarizedLeishmania-specific Th1 population by in vitro culture with IL-4. JImmunol 1995; 154:3779–87.

116. Majori M, Caminati A, Corradi M, et al. T-cell cytokine pattern atthree time points during specific immunotherapy for mite-sensitiveasthma. Clin Exp Allergy 2000; 30:341–7.

117. Lohoff M, Sommer F, Solbach W, et al. Coexistence of antigen-specificTH1 and TH2 cells in genetically susceptible BALB/c mice infectedwith Leishmania major. Immunobiology 1989; 179:412–21.

118. Bucy RP, Karr L, Huang GQ, et al. Single cell analysis of cytokinegene coexpression during CD41 T-cell phenotype development. ProcNatl Acad Sci USA 1995; 92:7565–9.

119. Graham CM, Smith CA, Thomas DB. Novel diversity in Th1, Th2type differentiation of hemagglutinin-specific T cell clones elicited bynatural influenza virus infection in three major haplotypes (H-2b,d,k).J Immunol 1998; 161:1094–103.

120. Clerici M, Shearer GM. The Th1-Th2 hypothesis of HIV infection:new insights. Immunol Today 1994; 15:575–81.

121. Daynes RA, Araneo BA, Dowell TA, et al. Regulation of murine lym-phokine production in vivo. III. The lymphoid tissue microenviron-ment exerts regulatory influences over T helper cell function. J ExpMed 1990; 171:979–96.

122. van der Poll T, Barber AE, Coyle SM, et al. Hypercortisolemia in-creases plasma interleukin-10 concentrations during human endo-toxemia: a clinical research center study. J Clin Endocrinol Metab1996; 81:3604–6.

123. Ramırez F. Glucocorticoids induce a Th2 response in vitro. Dev Im-munol 1998; 6:233–43.

124. Krakauer T. Differential inhibitory effects of interleukin-10, interleu-kin-4, and dexamethasone on staphylococcal enterotoxin–induced cy-tokine production and T cell activation. J Leukoc Biol 1995; 57:450–4.

125. Larsson S, Linden M. Effects of a corticosteroid, budesonide, on pro-duction of bioactive IL-12 by human monocytes. Cytokine 1998; 10:786–9.

126. Vieira PL, Kalinski P, Wierenga EA, et al. Glucocorticoids inhibitbioactive IL-12p70 production by in vitro–generated human dendritic

Dow




cells without affecting their T cell stimulatory potential. J Immunol1998; 161:5245–51.

127. Franchimont D, Galon J, Gadina M, et al. Inhibition of Th1 immuneresponse by glucocorticoids: dexamethasone selectively inhibits IL-12–induced Stat4 phosphorylation in T lymphocytes. J Immunol2000; 164:1768–74.

128. Boumpas DT, Anastassiou ED, Older SA, et al. Dexamethasone in-hibits human interleukin 2 but not interleukin 2 receptor gene ex-pression in vitro at the level of nuclear transcription. J Clin Invest1991; 87:1739–47.

129. Sierra-Honigmann MR, Murphy PA. T cell receptor–independent im-munosuppression induced by dexamethasone in murine T helpercells. J Clin Invest 1992; 89:556–60.

130. Zacharchuk CM, Mercep M, Chakraborti PK, et al. Programmed Tlymphocyte death: cell activation– and steroid-induced pathways aremutually antagonistic. J Immunol 1990; 145:4037–45.

131. Brinkmann V, Kristofic C. Regulation by corticosteroids of Th1 andTh2 cytokine production in human CD41 effector T cells generatedfrom CD45RO- and CD45RO1 subsets. J Immunol 1995; 155:3322–8.

132. Moynihan JA, Callahan TA, Kelley SP, et al. Adrenal hormone mod-ulation of type 1 and type 2 cytokine production by spleen cells:dexamethasone and dehydroepiandrosterone suppress interleukin-2,interleukin-4, and interferon-gamma production in vitro. Cell Im-munol 1998; 184:58–64.

133. Poznansky MC, Gordon AC, Douglas JG, et al. Resistance to meth-ylprednisolone in cultures of blood mononuclear cells from gluco-corticoid-resistant asthmatic patients. Clinical Science 1984; 67:639–45.

134. Almawi WY, Saouda MS, Stevens AC, et al. Partial mediation ofglucocorticoid antiproliferative effects by lipocortins. J Immunol1996; 157:5231–9.

135. Collins JV, Clark TJ, Brown D, et al. The use of corticosteroids in thetreatment of acute asthma. Q J Med 1975; 44:259–73.

136. Frey BM, Walker C, Frey FJ, et al. Pharmacokinetics and pharma-codynamics of three different prednisolone prodrugs: effect on cir-culating lymphocyte subsets and function. J Immunol 1984; 133:2479–87.

137. Guilbert LJ. There is a bias against type 1 (inflammatory) cytokineexpression and function in pregnancy. J Reprod Immunol 1996; 32:105–10.

138. Szekeres-Bartho J, Wegmann TG. A progesterone-dependent im-munomodulatory protein alters the Th1/Th2 balance. J Reprod Im-munol 1996; 31:81–95.

139. Kanda N, Tamaki K. Estrogen enhances immunoglobulin productionby human PBMCs. J Allergy Clin Immunol 1999; 103:282–8.

140. Chaouat G, Assal Meliani A, Martal J, et al. IL-10 prevents naturallyoccurring fetal loss in the CBA 3 DBA/2 mating combination, andlocal defect in IL-10 production in this abortion-prone combinationis corrected by in vivo injection of IFN-tau. J Immunol 1995; 154:4261–8.

141. Bennett WA, Lagoo-Deenadayalan S, Whitworth NS, et al. Expressionand production of interleukin-10 by human trophoblast: relationshipto pregnancy immunotolerance. Early Pregnancy 1997; 3:190–8.

142. Sabahi F, Rola-Plesczcynski M, O’Connell S, et al. Qualitative andquantitative analysis of T lymphocytes during normal human preg-nancy. Am J Reprod Immunol 1995; 33:381–93.

143. Darmochwal-Kolarz D, Leszczynska-Gorzelak B, Rolinski J, et al. Thelper 1– and T helper 2–type cytokine imbalance in pregnant womenwith pre-eclampsia. Eur J Obstet Gynecol Reprod Biol 1999; 86:165–70.

144. Saito S, Sakai M, Sasaki Y, et al. Quantitative analysis of peripheralblood Th0, Th1, Th2 and the Th1:Th2 cell ratio during normal humanpregnancy and preeclampsia. Clin Exp Immunol 1999; 117:550–5.

145. Hill JA, Polgar K, Anderson DJ. T-helper 1–type immunity to tro-phoblast in women with recurrent spontaneous abortion. JAMA1995; 273:1933–6.

146. Krishnan L, Guilbert LJ, Wegmann TG, et al. T helper 1 response

against Leishmania major in pregnant C57BL/6 mice increases im-plantation failure and fetal resorptions. Correlation with increasedIFN-gamma and TNF and reduced IL-10 production by placentalcells. J Immunol 1996; 156:653–62.

147. Raghupathy R, Makhseed M, Azizieh F, et al. Maternal Th1- and Th2-type reactivity to placental antigens in normal human pregnancy andunexplained recurrent spontaneous abortions. Cell Immunol 1999;196:122–30.

148. Daynes RA, Dudley DJ, Araneo BA. Regulation of murine lymphokineproduction in vivo. II. Dehydroepiandrosterone is a natural enhancerof interleukin 2 synthesis by helper T cells. Eur J Immunol 1990; 20:793–802.

149. Suzuki T, Suzuki N, Daynes RA, et al. Dehydroepiandrosterone en-hances IL2 production and cytotoxic effector function of human Tcells. Clin Immunol Immunopathol 1991; 61:202–11.

150. Kim HR, Ryu SY, Kim HS, et al. Administration of dehydroepian-drosterone reverses the immune suppression induced by high doseantigen in mice. Immunol Invest 1995; 24:583–93.

151. Huber SA, Pfaeffle B. Differential Th1 and Th2 cell responses in maleand female BALB/c mice infected with coxsackievirus group B type3. J Virol 1994; 68:5126–32.

152. Hadden JW, Hadden EM, Middleton E Jr. Lymphocyte blast trans-formation. I. Demonstration of adrenergic receptors in human pe-ripheral lymphocytes. Cell Immunol 1970; 1:583–95.

153. Sanders VM, Baker RA, Ramer-Quinn DS, et al. Differential expres-sion of the b2-adrenergic receptor by Th1 and Th2 clones: implica-tions for cytokine production and B cell help. J Immunol 1997; 158:4200–10.

154. Coqueret O, Petit-Frere C, Lagente V, et al. Modulation of IgE pro-duction in the mouse by b2-adrenoceptor agonist. Int Arch AllergyImmunol 1994; 105:171–6.

155. Suberville S, Bellocq A, Fouqueray B, et al. Regulation of interleukin-10 production by b-adrenergic agonists. Eur J Immunol 1996; 26:2601–5.

156. Elenkov IJ, Papanicolaou DA, Wilder RL, et al. Modulatory effectsof glucocorticoids and catecholamines on human interleukin-12 andinterleukin-10 production: clinical implications. Proc Assoc Am Phy-sicians 1996; 108:374–81.

157. van der Poll T, Coyle SM, Barbosa K, et al. Epinephrine inhibits tumornecrosis factor–alpha and potentiates interleukin 10 production dur-ing human endotoxemia. J Clin Invest 1996; 97:713–9.

158. Platzer C, Docke W, Volk H, et al. Catecholamines trigger IL-10 releasein acute systemic stress reaction by direct stimulation of its promoter/enhancer activity in monocytic cells. J Neuroimmunol 2000; 105:31–8.

159. Ramer-Quinn DS, Baker RA, Sanders VM. Activated T helper 1 andT helper 2 cells differentially express the b2-adrenergic receptor: amechanism for selective modulation of T helper 1 cell cytokine pro-duction. J Immunol 1997; 159:4857–67.

160. Fabris N, Piantanelli L, Muzzioli M. Differential effect of pregnancyor gestagens on humoral and cell-mediated immunity. Clin Exp Im-munol 1977; 28:306–14.

161. Betz M, Fox BS. Prostaglandin E2 inhibits production of Th1 lym-phokines but not of Th2 lymphokines. J Immunol 1991; 146:108–13.

162. van der Pouw Kraan TC, Boeije LC, Smeenk RJ, et al. Prostaglandin-E2 is a potent inhibitor of human interleukin 12 production. J ExpMed 1995; 181:775–9.

163. Katamura K, Shintaku N, Yamauchi Y, et al. Prostaglandin E2 atpriming of naive CD41 T cells inhibits acquisition of ability to produceIFN-gamma and IL-2, but not IL-4 and IL-5. J Immunol 1995; 155:4604–12.

164. Misra N, Selvakumar M, Singh S, et al. Monocyte derived IL 10 andPGE2 are associated with the absence of Th 1 cells and in vitro T cellsuppression in lepromatous leprosy. Immunol Lett 1995; 48:123–8.

165. Shimizu T, Streilein JW. Influence of alpha-melanocyte stimulatinghormone on induction of contact hypersensitivity and tolerance. JDermatol Sci 1994; 8:187–93.

166. Taylor AW, Streilein JW, Cousins SW. Alpha-melanocyte–stimulating

Dow




hormone suppresses antigen-stimulated T cell production of gamma-interferon. Neuroimmunomodulation 1994; 1:188–94.

167. Metchnikoff E. Immunity in infective diseases. Binnie, FG, trans.Cambridge: Cambridge University Press, 1905. Reprint: The sourcesof science, no. 61. New York: Johnson Reprint Corporation, 1968:166–7.

168. Lee WM. Hepatitis B virus infection. N Engl J Med 1997; 337:1733–45.169. Fukuda R, Ishimura N, Nguyen TX, et al. The expression of IL-2, IL-

4 and interferon-gamma (IFN-gamma) mRNA using liver biopsies atdifferent phases of acute exacerbation of chronic hepatitis B. Clin ExpImmunol 1995; 100:446–51.

170. Quiroga JA, Martın J, Navas S, et al. Induction of interleukin-12production in chronic hepatitis C virus infection correlates with thehepatocellular damage. J Infect Dis 1998; 178:247–51.

171. Takehara T, Hayashi N, Katayama K, et al. Hepatitis B core anti-gen–specific interferon gamma production of peripheral blood mon-onuclear cells during acute exacerbation of chronic hepatitis B. ScandJ Gastroenterol 1992; 27:727–31.

172. Lohr HF, Schmitz D, Arenz M, et al. The viral clearance in interferon-treated chronic hepatitis C is associated with increased cytotoxic Tcell frequencies. J Hepatol 1999; 31:407–15.

173. Laskus T, Radkowski M, Slusarczyk J, et al. Severe exacerbation ofchronic active hepatitis B during interferon alpha therapy. Digestion1992; 52:61–4.

174. Marcellin P, Colin JF, Boyer N, et al. Fatal exacerbation of chronichepatitis B induced by recombinant alpha-interferon. Lancet 1991;338:828.

175. Shindo M, Di Bisceglie AM, Hoofnagle JH. Acute exacerbation ofliver disease during interferon alfa therapy for chronic hepatitis C.Gastroenterology 1992; 102:1406–8.

176. van der Watt M, Lemmer E, Robson SC. Exacerbation of liver diseaseduring interferon-alpha therapy for chronic hepatitis C. South AfricanMedical Journal 1994; 84:509.

177. Livingston BD, Alexander J, Crimi C, et al. Altered helper T lym-phocyte function associated with chronic hepatitis B virus infectionand its role in response to therapeutic vaccination in humans. J Im-munol 1999; 162:3088–95.

178. Boni C, Bertoletti A, Penna A, et al. Lamivudine treatment can restoreT cell responsiveness in chronic hepatitis B. J Clin Invest 1998; 102:968–75.

179. Aloisi F, Ria F, Columba-Cabezas S, et al. Relative efficiency of mi-croglia, astrocytes, dendritic cells and B cells in naive CD41 T cellpriming and Th1/Th2 cell restimulation. Eur J Immunol 1999; 29:2705–14.

180. Liano D, Abbas AK. Antigen presentation by hapten-specific B lym-phocytes. V. Requirements for activation of antigen-presenting B cells.J Immunol 1987; 139:2562–6.

181. Stockinger B, Zal T, Zal A, et al. B cells solicit their own help fromT cells. J Exp Med 1996; 183:891–9.

182. Skok J, Poudrier J, Gray D. Dendritic cell–derived IL-12 promotes Bcell induction of Th2 differentiation: a feedback regulation of Th1development. J Immunol 1999; 163:4284–91.

183. Schmitz J, Assenmacher M, Radbruch A. Regulation of T helper cellcytokine expression: functional dichotomy of antigen-presenting cells.Eur J Immunol 1993; 23:191–9.

184. Croft M, Duncan DD, Swain SL. Response of naive antigen-specificCD41 T cells in vitro: characteristics and antigen-presenting cell re-quirements. J Exp Med 1992; 176:1431–7.

185. Cassell DJ, Schwartz RH. A quantitative analysis of antigen-presentingcell function: activated B cells stimulate naive CD4 T cells but areinferior to dendritic cells in providing costimulation. J Exp Med1994; 180:1829–40.

186. Masten BJ, Lipscomb MF. Comparison of lung dendritic cells and Bcells in stimulating naive antigen-specific T cells. J Immunol 1999;162:1310–7.

187. Hilkens CM, Kalinski P, de Boer M, et al. Human dendritic cells

require exogenous interleukin-12-inducing factors to direct the de-velopment of naive T-helper cells toward the Th1 phenotype. Blood1997; 90:1920–6.

188. Kalinski P, Hilkens CM, Snijders A, et al. IL-12-deficient dendriticcells, generated in the presence of prostaglandin E2, promote type 2cytokine production in maturing human naive T helper cells. J Im-munol 1997; 159:28–35.

189. Liu L, Rich BE, Inobe J, et al. Induction of Th2 cell differentiationin the primary immune response: dendritic cells isolated from ad-herent cell culture treated with IL-10 prime naive CD41 T cells tosecrete IL-4. Int Immunol 1998; 10:1017–26.

190. Kapsenberg ML, Kalinski P. The concept of type 1 and type 2 antigen-presenting cells. Immunol Lett 1999; 69:5–6.

191. Lenschow DJ, Walunas TL, Bluestone JA. CD28/B7 system of T cellcostimulation. Annu Rev Immunol 1996; 14:233–58.

192. Tao X, Constant S, Jorritsma P, et al. Strength of TCR signal deter-mines the costimulatory requirements for Th1 and Th2 CD41 T celldifferentiation. J Immunol 1997; 159:5956–63.

193. Iezzi G, Scotet E, Scheidegger D, et al. The interplay between theduration of TCR and cytokine signaling determines T cell polarization.Eur J Immunol 1999; 29:4092–101.

194. Richter A, Lohning M, Radbruch A. Instruction for cytokine expres-sion in T helper lymphocytes in relation to proliferation and cell cycleprogression. J Exp Med 1999; 190:1439–50.

195. Rogers PR, Croft M. Peptide dose, affinity, and time of differentiationcan contribute to the Th1/Th2 cytokine balance. J Immunol 1999;163:1205–13.

196. Matzinger P. An innate sense of danger. Seminars in Immunology1998; 10:399–415.

197. Skeen MJ, Miller MA, Shinnick TM, et al. Regulation of murinemacrophage IL-12 production: activation of macrophages in vivo,restimulation in vitro, and modulation by other cytokines. J Immunol1996; 156:1196–206.

198. Cleveland MG, Gorham JD, Murphy TL, et al. Lipotechoic acid prep-arations of gram-positive bacteria induce interleukin-12 through aCD14-dependent pathway. Infect Immun 1996; 64:1906–12.

199. Pisetsky DS. The influence of base sequence on the immunostimu-latory properties of DNA. Immunologic Research 1999; 19:35–46.

200. Yamamoto S, Yamamoto T, Shimada S, et al. DNA from bacteria, butnot from vertebrates, induces interferons, activates natural killer cellsand inhibits tumor growth. Microbiol Immunol 1992; 36:983–97.

201. Krieg AM, Yi AK, Matson S, et al. CpG motifs in bacterial DNAtrigger direct B-cell activation. Nature 1995; 374:546–9.

202. Chace JH, Hooker NA, Mildenstein KL, et al. Bacterial DNA-inducedNK cell IFN-gamma production is dependent on macrophage secre-tion of IL-12. Clin Immunol Immunopathol 1997; 84:185–93.

203. Krieg AM, Love-Homan L, Yi AK, et al. CpG DNA induces sustainedIL-12 expression in vivo and resistance to Listeria monocytogenes chal-lenge. J Immunol 1998; 161:2428–34.

204. Sparwasser T, Koch ES, Vabulas RM, et al. Bacterial DNA and im-munostimulatory CpG oligonucleotides trigger maturation and ac-tivation of murine dendritic cells. Eur J Immunol 1998; 28:2045–54.

205. Cowdery JS, Boerth NJ, Norian LA, et al. Differential regulation ofthe IL-12 p40 promoter and of p40 secretion by CpG DNA andlipopolysaccharide. J Immunol 1999; 162:6770–5.

206. Neujahr DC, Reich CF, Pisetsky DS. Immunostimulatory propertiesof genomic DNA from different bacterial species. Immunobiology1999; 200:106–19.

207. Bliss SK, Marshall AJ, Zhang Y, et al. Human polymorphonuclearleukocytes produce IL-12, TNF-a, and the chemokines macrophage-inflammatory protein–1a and –1b in response to Toxoplasma gondiiantigens. J Immunol 1999; 162:7369–75.

208. Wang J, Wakeham J, Harkness R, et al. Macrophages are a significantsource of type 1 cytokines during mycobacterial infection. J Clin Invest1999; 103:1023–9.

209. Chen W, Syldath U, Bellmann K, et al. Human 60-kDa heat-shock

Dow




protein: a danger signal to the innate immune system. J Immunol1999; 162:3212–9.

210. Kruskal BA, Maxfield FR. Cytosolic free calcium increases before andoscillates during frustrated phagocytosis in macrophages. J Cell Biol1987; 105:2685–93.

211. Bainton DF, Takemura R, Stenberg PE, et al. Rapid fragmentationand reorganization of Golgi membranes during frustrated phagocy-tosis of immobile immune complexes by macrophages. Am J Pathol1989; 134:15–26.

212. Gardiner EE, Mok SS, Sriratana A, et al. Polymorphonuclear neutro-phils release 35S-labelled proteoglycans into cartilage during frus-trated phagocytosis. Eur J Biochem 1994; 221:871–9.

213. Holevinsky KO, Nelson DJ. Membrane capacitance changes associatedwith particle uptake during phagocytosis in macrophages. Biophys J1998; 75:2577–86.

214. Romani L, Mencacci A, Cenci E, et al. An immunoregulatory role forneutrophils in CD41 T helper subset selection in mice with candi-diasis. J Immunol 1997; 158:2356–62.

215. Flesch IE, Hess JH, Huang S, et al. Early interleukin 12 productionby macrophages in response to mycobacterial infection depends oninterferon gamma and tumor necrosis factor alpha. J Exp Med1995; 181:1615–21.

216. Libraty DH, Airan LE, Uyemura K, et al. Interferon-gamma differ-entially regulates interleukin-12 and interleukin-10 production in lep-rosy. J Clin Invest 1997; 99:336–41.

217. de Waal Malefyt R. The role of type I interferons in the differentiationand function of Th1 and Th2 cells. Semin Oncol 1997; 24:S9–94–S9–8.

218. Emoto M, Emoto Y, Buchwalow IB, et al. Induction of IFN-gamma-producing CD41 natural killer T cells by Mycobacterium bovis bacillusCalmette Guerin. Eur J Immunol 1999; 29:650–9.

219. Yao BB, Niu P, Surowy CS, et al. Direct interaction of STAT4 withthe IL-12 receptor. Arch Biochem Biophys 1999; 368:147–55.

220. Bacon CM, Petricoin EF 3rd, Ortaldo JR, et al. Interleukin 12 inducestyrosine phosphorylation and activation of STAT4 in human lym-phocytes. Proc Natl Acad Sci USA 1995; 92:7307–11.

221. Hou J, Schindler U, Henzel WJ, et al. An interleukin-4-induced tran-scription factor: IL-4 Stat. Science 1994; 265:1701–6.

222. Lederer JA, Perez VL, DesRoches L, et al. Cytokine transcriptionalevents during helper T cell subset differentiation. J Exp Med 1996;184:397–406.

223. Kaplan MH, Sun YL, Hoey T, et al. Impaired IL-12 responses andenhanced development of Th2 cells in Stat4-deficient mice. Nature1996; 382:174–7.

224. Thierfelder WE, van Deursen JM, Yamamoto K, et al. Requirementfor Stat4 in interleukin-12-mediated responses of natural killer andT cells. Nature 1996; 382:171–4.

225. Shimoda K, van Deursen J, Sangster MY, et al. Lack of IL-4-inducedTh2 response and IgE class switching in mice with disrupted Stat6gene. Nature 1996; 380:630–3.

226. Takeda K, Tanaka T, Shi W, et al. Essential role of Stat6 in IL-4signalling. Nature 1996; 380:627–30.

227. Zhang DH, Cohn L, Ray P, et al. Transcription factor GATA-3 isdifferentially expressed in murine Th1 and Th2 cells and controlsTh2-specific expression of the interleukin-5 gene. J Biol Chem1997; 272:21597–603.

228. Zheng W, Flavell RA. The transcription factor GATA-3 is necessaryand sufficient for Th2 cytokine gene expression in CD4 T cells. Cell1997; 89:587–96.

229. Ouyang W, Lohning M, Gao Z, et al. Stat6-independent GATA-3autoactivation directs IL-4-independent Th2 development and com-mitment. Immunity 2000; 12:27–37.

230. Ouyang W, Jacobson NG, Bhattacharya D, et al. The Ets transcriptionfactor ERM is Th1-specific and induced by IL-12 through a Stat4-dependent pathway. Proc Natl Acad Sci USA 1999; 96:3888–93.

231. Szabo SJ, Kim ST, Costa GL, et al. A novel transcription factor, T-bet, directs Th1 lineage commitment. Cell 2000; 100:655–69.

232. Alleva DG, Kaser SB, Beller DI. Intrinsic defects in macrophage IL-12 production associated with immune dysfunction in the MRL/11and New Zealand black/white F1 lupus-prone mice and the Leish-mania major–susceptible BALB/c strain. J Immunol 1998; 161:6878–84.

233. Himmelrich H, Parra-Lopez C, Tacchini-Cottier F, et al. The IL-4rapidly produced in BALB/c mice after infection with Leishmaniamajor down-regulates IL-12 receptor b-2-chain expression on CD41

T cells, resulting in a state of unresponsiveness to IL-12. J Immunol1998; 161:6156–63.

234. Sadick MD, Locksley RM, Tubbs C, et al. Murine cutaneous leish-maniasis: resistance correlates with the capacity to generate interferon-gamma in response to Leishmania antigens in vitro. J Immunol1986; 136:655–61.

235. Locksley RM, Heinzel FP, Sadick MD, et al. Murine cutaneous leish-maniasis: susceptibility correlates with differential expansion of helperT-cell subsets. Ann Inst Pasteur Immunol 1987; 138:744–9.

236. Heinzel FP, Sadick MD, Locksley RM. Leishmania major: analysis oflymphocyte and macrophage cellular phenotypes during infection ofsusceptible and resistant mice. Exp Parasitol 1988; 65:258–68.

237. Scott P, Natovitz P, Coffman RL, et al. Immunoregulation of cutaneousleishmaniasis. T cell lines that transfer protective immunity or ex-acerbation belong to different T helper subsets and respond to distinctparasite antigens. J Exp Med 1988; 168:1675–84.

238. Heinzel FP, Sadick MD, Holaday BJ, et al. Reciprocal expression ofinterferon gamma or interleukin 4 during the resolution or progres-sion of murine leishmaniasis: evidence for expansion of distinct helperT cell subsets. J Exp Med 1989; 169:59–72.

239. Heinzel FP, Sadick MD, Mutha SS, et al. Production of interferongamma, interleukin 2, interleukin 4, and interleukin 10 by CD41

lymphocytes in vivo during healing and progressive murine leish-maniasis. Proc Natl Acad Sci USA 1991; 88:7011–5.

240. Kopf M, Brombacher F, Kohler G, et al. IL-4-deficient Balb/c miceresist infection with Leishmania major. J Exp Med 1996; 184:1127–36.

241. Stamm LM, Raisanen-Sokolowski A, Okano M, et al. Mice withSTAT6-targeted gene disruption develop a Th1 response and controlcutaneous leishmaniasis. J Immunol 1998; 161:6180–8.

242. Chatelain R, Mauze S, Varkila K, et al. Leishmania major infection ininterleukin-4 and interferon-gamma depleted mice. Parasite Immunol1999; 21:423–31.

243. Krishnan L, Guilbert LJ, Russell AS, et al. Pregnancy impairs resistanceof C57BL/6 mice to Leishmania major infection and causes decreasedantigen-specific IFN-gamma response and increased production of Thelper 2 cytokines. J Immunol 1996; 156:644–52.

244. Constantinescu CS, Hondowicz BD, Elloso MM, et al. The role ofIL-12 in the maintenance of an established Th1 immune response inexperimental leishmaniasis. Eur J Immunol 1998; 28:2227–33.

245. Holaday BJ, Sadick MD, Wang ZE, et al. Reconstitution of Leishmaniaimmunity in severe combined immunodeficient mice using Th1- andTh2-like cell lines. J Immunol 1991; 147:1653–8.

246. Yssel H, Fasler S, de Vries JE, et al. IL-12 transiently induces IFN-gamma transcription and protein synthesis in human CD41 allergen-specific Th2 T cell clones. Int Immunol 1994; 6:1091–6.

247. Nabors GS, Afonso LC, Farrell JP, et al. Switch from a type 2 to atype 1 T helper cell response and cure of established Leishmania majorinfection in mice is induced by combined therapy with interleukin12 and pentostam. Proc Natl Acad Sci USA 1995; 92:3142–6.

248. Bretscher PA, Wei G, Menon JN, et al. Establishment of stable, cell-mediated immunity that makes “susceptible” mice resistant to Leish-mania major. Science 1992; 257:539–42.

249. Menon JN, Bretscher PA. Parasite dose determines the Th1/Th2 natureof the response to Leishmania major independently of infection routeand strain of host or parasite. Eur J Immunol 1998; 28:4020–8.

250. Pashine A, John B, Rath S, et al. Th1 dominance in the immuneresponse to live Salmonella typhimurium requires bacterial invasive-ness but not persistence. Int Immunol 1999; 11:481–9.

Dow




251. Bao S, Beagley KW, France MP, et al. Interferon-gamma plays a criticalrole in intestinal immunity against Salmonella typhimurium infection.Immunology 2000; 99:464–72.

252. Chopra U, Vohra H, Chibber S, et al. Th1 pattern of cytokine secretionby splenic cells from pyelonephritic mice after in-vitro stimulationwith hsp-65 of Escherichia coli. J Med Microbiol 1997; 46:139–44.

253. Miller MA, Skeen MJ, Ziegler HK. Long-lived protective immunityto Listeria is conferred by immunization with particulate or solublelisterial antigen preparations coadministered with IL-12. Cell Im-munol 1998; 184:92–104.

254. Yeung VP, Gieni RS, Umetsu DT, et al. Heat-killed Listeria monocy-togenes as an adjuvant converts established murine Th2-dominatedimmune responses into Th1-dominated responses. J Immunol1998; 161:4146–52.

255. Dai WJ, Kohler G, Brombacher F. Both innate and acquired immunityto Listeria monocytogenes infection are increased in IL-10-deficientmice. J Immunol 1997; 158:2259–67.

256. Ferrick DA, Schrenzel MD, Mulvania T, et al. Differential productionof interferon-gamma and interleukin-4 in response to Th1- and Th2-stimulating pathogens by gamma delta T cells in vivo. Nature1995; 373:255–7.

257. Moser C, Johansen HK, Song Z, et al. Chronic Pseudomonas aeru-ginosa lung infection is more severe in Th2 responding BALB/c micecompared to Th1 responding C3H/HeN mice. APMIS 1997; 105:838–42.

258. Johansen HK, Cryz SJ Jr, Hougen HP, et al. Vaccination promotesTh1-like inflammation and survival in chronic Pseudomonas aerugi-nosa pneumonia: a new prophylactic principle. Behring Inst Mitt1997; 41:269–73.

259. ten Hagen TL, van Vianen W, Savelkoul HF, et al. Involvement of Tcells in enhanced resistance to Klebsiella pneumoniae septicemia inmice treated with liposome-encapsulated muramyl tripeptide phos-phatidylethanolamine or gamma interferon. Infect Immun 1998; 66:1962–7.

260. Brennan FR, Jones TD, Gilleland LB, et al. Pseudomonas aeruginosaouter-membrane protein F epitopes are highly immunogenic in micewhen expressed on a plant virus. Microbiology 1999; 145:211–20.

261. Hein J, Kempf VA, Diebold J, et al. Interferon consensus sequencebinding protein confers resistance against Yersinia enterocolitica. InfectImmun 2000; 68:1408–17.

262. Kobayashi K, Kai M, Gidoh M, et al. The possible role of interleukin(IL)-12 and interferon-gamma–inducing factor/IL-18 in protectionagainst experimental Mycobacterium leprae infection in mice. ClinImmunol Immunopathol 1998; 88:226–31.

263. Sugawara I, Yamada H, Kaneko H, et al. Role of interleukin-18 (IL-18) in mycobacterial infection in IL-18-gene-disrupted mice. InfectImmun 1999; 67:2585–9.

264. Orme IM, Roberts AD, Griffin JP, et al. Cytokine secretion by CD4T lymphocytes acquired in response to Mycobacterium tuberculosisinfection. J Immunol 1993; 151:518–25.

265. Romani L, Cenci E, Mencacci A, et al. Gamma interferon modifiesCD41 subset expression in murine candidiasis. Infect Immun 1992;60:4950–2.

266. Mencacci A, Romani L, Mosci P, et al. Low-dose streptozotocin-induced diabetes in mice. II. Susceptibility to Candida albicans in-fection correlates with the induction of a biased Th2-like antifungalresponse. Cell Immunol 1993; 150:36–44.

267. Magee DM, Cox RA. Interleukin-12 regulation of host defenses againstCoccidioides immitis. Infect Immun 1996; 64:3609–13.

268. Cenci E, Perito S, Enssle KH, et al. Th1 and Th2 cytokines in micewith invasive aspergillosis. Infect Immun 1997; 65:564–70.

269. Decken K, Kohler G, Palmer-Lehmann K, et al. Interleukin-12 isessential for a protective Th1 response in mice infected with Cryp-tococcus neoformans. Infect Immun 1998; 66:4994–5000.

270. Abuodeh RO, Shubitz LF, Siegel E, et al. Resistance to Coccidioidesimmitis in mice after immunization with recombinant protein or a

DNA vaccine of a proline-rich antigen. Infect Immun 1999; 67:2935–40.

271. Romani L, Mencacci A, Grohmann U, et al. Neutralizing antibodyto interleukin 4 induces systemic protection and T helper type 1–as-sociated immunity in murine candidiasis. J Exp Med 1992; 176:19–25.

272. Mencacci A, Spaccapelo R, Del Sero G, et al. CD41 T-helper-cellresponses in mice with low-level Candida albicans infection. InfectImmun 1996; 64:4907–14.

273. Cenci E, Mencacci A, Del Sero G, et al. Induction of protective Th1responses to Candida albicans by antifungal therapy alone or in com-bination with an interleukin-4 antagonist. J Infect Dis 1997; 176:217–26.

274. Mencacci A, Cenci E, Bacci A, et al. Host immune reactivity deter-mines the efficacy of combination immunotherapy and antifungalchemotherapy in candidiasis. J Infect Dis 2000; 181:686–94.

275. Else KJ, Grencis RK. Cellular immune responses to the murine nem-atode parasite Trichuris muris. I. Differential cytokine production dur-ing acute or chronic infection. Immunology 1991; 72:508–13.

276. Grencis RK, Hultner L, Else KJ. Host protective immunity to Tri-chinella spiralis in mice: activation of Th cell subsets and lymphokinesecretion in mice expressing different response phenotypes. Immu-nology 1991; 74:329–32.

277. Else KJ, Hultner L, Grencis RK. Cellular immune responses to themurine nematode parasite Trichuris muris. II. Differential inductionof Th-cell subsets in resistant versus susceptible mice. Immunology1992; 75:232–7.

278. Else KJ, Entwistle GM, Grencis RK. Correlations between worm bur-den and markers of Th1 and Th2 cell subset induction in an inbredstrain of mouse infected with Trichuris muris. Parasite Immunol1993; 15:595–600.

279. Tuohy M, Lammas DA, Wakelin D, et al. Functional correlationsbetween mucosal mast cell activity and immunity to Trichinella spiralisin high and low responder mice. Parasite Immunol 1990; 12:675–85.

280. Grencis RK, Else KJ, Huntley JF, et al. The in vivo role of stem cellfactor (c-kit ligand) on mastocytosis and host protective immunityto the intestinal nematode Trichinella spiralis in mice. Parasite Im-munol 1993; 15:55–9.

281. Urban JF Jr, Schopf L, Morris SC, et al. Stat6 signaling promotesprotective immunity against Trichinella spiralis through a mast cell–and T cell–dependent mechanism. J Immunol 2000; 164:2046–52.

282. Faulkner H, Renauld JC, Van Snick J, et al. Interleukin-9 enhancesresistance to the intestinal nematode Trichuris muris. Infect Immun1998; 66:3832–40.

283. Faulkner H, Humphreys N, Renauld JC, et al. Interleukin-9 is involvedin host protective immunity to intestinal nematode infection. Eur JImmunol 1997; 27:2536–40.

284. Richard M, Grencis RK, Humphreys NE, et al. Anti-IL-9 vaccinationprevents worm expulsion and blood eosinophilia in Trichurismuris–infected mice. Proc Natl Acad Sci USA 2000; 97:767–72.

285. Else KJ, Finkelman FD, Maliszewski CR, et al. Cytokine-mediatedregulation of chronic intestinal helminth infection. J Exp Med1994; 179:347–51.

286. Finkelman FD, Madden KB, Cheever AW, et al. Effects of interleukin12 on immune responses and host protection in mice infected withintestinal nematode parasites. J Exp Med 1994; 179:1563–72.

287. Bancroft AJ, Else KJ, Sypek JP, et al. Interleukin-12 promotes a chronicintestinal nematode infection. Eur J Immunol 1997; 27:866–70.

288. Sher A, Coffman RL. Regulation of immunity to parasites by T cellsand T cell–derived cytokines. Annu Rev Immunol 1992; 10:385–409.

289. Pond L, Wassom DL, Hayes CE. Evidence for differential inductionof helper T cell subsets during Trichinella spiralis infection. J Immunol1989; 143:4232–7.

290. Jankovic D, Kullberg MC, Dombrowicz D, et al. Fc epsilonRI–deficient mice infected with Schistosoma mansoni mount normal Th2-type responses while displaying enhanced liver pathology. J Immunol1997; 159:1868–75.

291. Kigoni EP, Elsas PP, Lenzi HL, et al. IgE antibody and resistance to

Dow




infection. II. Effect of IgE suppression on the early and late skinreaction and resistance of rats to Schistosoma mansoni infection. EurJ Immunol 1986; 16:589–95.

292. King CL, Malhotra I, Jia X. Schistosoma mansoni: protective immunityin IL-4-deficient mice. Exp Parasitol 1996; 84:245–52.

293. Sugane K, Oshima T. Interrelationship of eosinophilia and IgE an-tibody production to larval ES antigen in Toxocara canis infected mice.Parasite Immunol 1984; 6:409–20.

294. Uchikawa R, Ichiki H, Komaki E. Antibody responses and protectiveimmunity in rats receiving repeated inoculations of Strongyloides ratti.J Parasitol 1991; 77:737–41.

295. Needham CS, Lillywhite JE, Didier JM, et al. Temporal changes inTrichuris trichiura infection intensity and serum isotype responses inchildren. Parasitology 1994; 109:197–200.

296. Lawrence RA, Gray CA, Osborne J, et al. Nippostrongylus brasiliensis:cytokine responses and nematode expulsion in normal and IL-4-de-ficient mice. Exp Parasitol 1996; 84:65–73.

297. Bancroft AJ, McKenzie AN, Grencis RK. A critical role for IL-13 inresistance to intestinal nematode infection. J Immunol 1998; 160:3453–61.

298. Zurawski SM, Chomarat P, Djossou O, et al. The primary bindingsubunit of the human interleukin-4 receptor is also a component ofthe interleukin-13 receptor. J Biol Chem 1995; 270:13869–78.

299. Vita N, Lefort S, Laurent P, et al. Characterization and comparisonof the interleukin 13 receptor with the interleukin 4 receptor onseveral cell types. J Biol Chem 1995; 270:3512–7.

300. Kotowicz K, Callard RE, Friedrich K, et al. Biological activity of IL-4 and IL-13 on human endothelial cells: functional evidence that bothcytokines act through the same receptor. Int Immunol 1996; 8:1915–25.

301. Urban JF Jr, Noben-Trauth N, Donaldson DD, et al. IL-13, IL-4Ra,and Stat6 are required for the expulsion of the gastrointestinal nem-atode parasite Nippostrongylus brasiliensis. Immunity 1998; 8:255–64.

302. McKenzie GJ, Fallon PG, Emson CL, et al. Simultaneous disruptionof interleukin (IL)-4 and IL-13 defines individual roles in T helpercell type 2–mediated responses. J Exp Med 1999; 189:1565–72.

303. Artis D, Humphreys NE, Bancroft AJ, et al. Tumor necrosis factoralpha is a critical component of interleukin 13–mediated protectiveT helper cell type 2 responses during helminth infection. J Exp Med1999; 190:953–62.

304. Pirmez C, Yamamura M, Uyemura K, et al. Cytokine patterns in thepathogenesis of human leishmaniasis. J Clin Invest 1993; 91:1390–5.

305. Ghalib HW, Piuvezam MR, Skeiky YA, et al. Interleukin 10 productioncorrelates with pathology in human Leishmania donovani infections.J Clin Invest 1993; 92:324–9.

306. Kemp M, Handman E, Kemp K, et al. The Leishmania promastigotesurface antigen-2 (PSA-2) is specifically recognised by Th1 cells inhumans with naturally acquired immunity to L. major. Fems ImmunolMed Microbiol 1998; 20:209–18.

307. Carvalho EM, Bacellar O, Brownell C, et al. Restoration of IFN-gamma production and lymphocyte proliferation in visceral leish-maniasis. J Immunol 1994; 152:5949–56.

308. Agren K, Brauner A, Andersson J. Haemophilus influenzae and Strep-tococcus pyogenes group A challenge induce a Th1 type of cytokineresponse in cells obtained from tonsillar hypertrophy and recurrenttonsillitis. ORL J Otorhinolaryngol Rel Spec 1998; 60:35–41.

309. Follows GA, Munk ME, Gatrill AJ, et al. Gamma interferon andinterleukin 2, but not interleukin 4, are detectable in gamma/deltaT-cell cultures after activation with bacteria. Infect Immun 1992; 60:1229–31.

310. Miettinen M, Matikainen S, Vuopio-Varkila J, et al. Lactobacilli andstreptococci induce interleukin-12 (IL-12), IL-18, and gamma inter-feron production in human peripheral blood mononuclear cells. In-fect Immun 1998; 66:6058–62.

311. Kwak DJ, Augustine NH, Borges WG, et al. Intracellular and extra-cellular cytokine production by human mixed mononuclear cells inresponse to group B streptococci. Infect Immun 2000; 68:320–7.

312. Altare F, Lammas D, Revy P, et al. Inherited interleukin 12 deficiencyin a child with bacille Calmette-Guerin and Salmonella enteritidisdisseminated infection. J Clin Invest 1998; 102:2035–40.

313. de Jong R, Altare F, Haagen IA, et al. Severe mycobacterial and sal-monella infections in interleukin-12 receptor–deficient patients. Sci-ence 1998; 280:1435–8.

314. Haraguchi S, Day NK, Nelson RP Jr, et al. Interleukin 12 deficiencyassociated with recurrent infections. Proc Natl Acad Sci USA 1998;95:13125–9.

315. Roesler J, Kofink B, Wendisch J, et al. Listeria monocytogenes andrecurrent mycobacterial infections in a child with complete interferon-gamma-receptor (IFNgR1) deficiency: mutational analysis and eval-uation of therapeutic options. Exp Hematol 1999; 27:1368–74.

316. Sieling PA, Modlin RL. Cytokine patterns at the site of mycobacterialinfection. Immunobiology 1994; 191:378–87.

317. Misra N, Murtaza A, Walker B, et al. Cytokine profile of circulatingT cells of leprosy patients reflects both indiscriminate and polarizedT-helper subsets: T-helper phenotype is stable and uninfluenced byrelated antigens of Mycobacterium leprae. Immunology 1995; 86:97–103.

318. Lenzini L, Rottoli P, Rottoli L. The spectrum of human tuberculosis.Clin Exp Immunol 1977; 27:230–7.

319. David HL, Papa F, Cruaud P, et al. Relationships between titers ofantibodies immunoreacting against glycolipid antigens from Myco-bacterium leprae and M. tuberculosis, the Mitsuda and Mantoux re-actions, and bacteriological loads: implications in the pathogenesis,epidemiology and serodiagnosis of leprosy and tuberculosis. Int J LeprOther Mycobact Dis 1992; 60:208–24.

320. Sanchez FO, Rodrıguez JI, Agudelo G, et al. Immune responsivenessand lymphokine production in patients with tuberculosis and healthycontrols. Infect Immun 1994; 62:5673–8.

321. Surcel HM, Troye-Blomberg M, Paulie S, et al. Th1/Th2 profiles intuberculosis, based on the proliferation and cytokine response ofblood lymphocytes to mycobacterial antigens. Immunology 1994; 81:171–6.

322. Seah GT, Scott GM, Rook GA. Type 2 cytokine gene activation andits relationship to extent of disease in patients with tuberculosis. JInfect Dis 2000; 181:385–9.

323. Frucht DM, Holland SM. Defective monocyte costimulation for IFN-gamma production in familial disseminated Mycobacterium aviumcomplex infection: abnormal IL-12 regulation. J Immunol 1996; 157:411–6.

324. Jouanguy E, Altare F, Lamhamedi-Cherradi S, et al. Infections inIFNGR-1-deficient children. J Interferon Cytokine Res 1997; 17:583–7.

325. Pierre-Audigier C, Jouanguy E, Lamhamedi S, et al. Fatal disseminatedMycobacterium smegmatis infection in a child with inherited interferongamma receptor deficiency. Clin Infect Dis 1997; 24:982–4.

326. Holland SM, Dorman SE, Kwon A, et al. Abnormal regulation ofinterferon-gamma, interleukin-12, and tumor necrosis factor-alpha inhuman interferon-gamma receptor 1 deficiency. J Infect Dis 1998;178:1095–104.

327. Altare F, Durandy A, Lammas D, et al. Impairment of mycobacterialimmunity in human interleukin-12 receptor deficiency. Science1998; 280:1432–5.

328. Sander B, Skansen-Saphir U, Damm O, et al. Sequential productionof Th1 and Th2 cytokines in response to live bacillus Calmette-Guerin.Immunology 1995; 86:512–8.

329. Ausiello CM, Urbani F, Gessani S, et al. Cytokine gene expression inhuman peripheral blood mononuclear cells stimulated by manno-protein constituents from Candida albicans. Infect Immun 1993; 61:4105–11.

330. Lilic D, Cant AJ, Abinun M, et al. Chronic mucocutaneous candidiasis.I. Altered antigen-stimulated IL-2, IL-4, IL-6 and interferon-gamma(IFN-gamma) production. Clin Exp Immunol 1996; 105:205–12.

331. Roilides E, Kadiltsoglou I, Dimitriadou A, et al. Interleukin-4 sup-presses antifungal activity of human mononuclear phagocytes against

Dow




Candida albicans in association with decreased uptake of blastocon-idia. FEMS Immunol Med Microbiol 1997; 19:169–80.

332. Mouy R, Veber F, Blanche S, et al. Long-term itraconazole prophylaxisagainst aspergillus infections in thirty-two patients with chronic gran-ulomatous disease. J Pediatr 1994; 125:998–1003.

333. Rex JH, Bennett JE, Gallin JI, et al. In vivo interferon-gamma therapyaugments the in vitro ability of chronic granulomatous disease neu-trophils to damage Aspergillus hyphae. J Infect Dis 1991; 163:849–52.

334. A controlled trial of interferon gamma to prevent infection in chronicgranulomatous disease. The International Chronic GranulomatousDisease Cooperative Study Group. N Engl J Med 1991; 324:509–16.

335. Barcellini W, Rizzardi GP, Borghi MO, et al. Th1 and Th2 cytokineproduction by peripheral blood mononuclear cells from HIV-infectedpatients. AIDS 1994; 8:757–62.

336. Clerici M, Balotta C, Salvaggio A, et al. Human immunodeficiencyvirus (HIV) phenotype and interleukin-2/interleukin-10 ratio are as-sociated markers of protection and progression in HIV infection.Blood 1996; 88:574–9.

337. Johann-Liang R, Cervia J, Noel GJ. Endogenous interleukin-2 serumlevels in children infected with human immunodeficiency virus. ClinInfect Dis 1997; 25:1233–6.

338. Daftarian MP, Diaz-Mitoma F, Creery WD, et al. Dysregulated pro-duction of interleukin-10 (IL–10) and IL–12 by peripheral blood lym-phocytes from human immunodeficiency virus–infected individualsis associated with altered proliferative responses to recall antigens.Clin Diagn Lab Immunol 1995; 2:712–8.

339. Gazzinelli RT, Bala S, Stevens R, et al. HIV infection suppresses type1 lymphokine and IL-12 responses to Toxoplasma gondii but fails toinhibit the synthesis of other parasite-induced monokines. J Immunol1995; 155:1565–74.

340. Marshall JD, Chehimi J, Gri G, et al. The interleukin-12-mediatedpathway of immune events is dysfunctional in human immunode-ficiency virus–infected individuals. Blood 1999; 94:1003–11.

341. Clerici M, Lucey DR, Berzofsky JA, et al. Restoration of HIV-specificcell-mediated immune responses by interleukin-12 in vitro. Science1993; 262:1721–4.

342. Imami N, Antonopoulos C, Hardy GA, et al. Assessment of type 1and type 2 cytokines in HIV type 1–infected individuals: impact ofhighly active antiretroviral therapy. AIDS Res Hum Retroviruses1999; 15:1499–508.

343. Weiss L, Ancuta P, Girard PM, et al. Restoration of normal interleukin-2 production by CD41 T cells of human immunodeficiency vi-rus–infected patients after 9 months of highly active antiretroviraltherapy. J Infect Dis 1999; 180:1057–63.

344. Voiculescu C, Avramescu C, Radu E, et al. Current laboratory assaysand in vitro intracellular Th1 and Th2 cytokine synthesis in moni-toring antiretroviral therapy of pediatric HIV infection. FEMS Im-munol Med Microbiol 2000; 27:67–71.

345. Loetscher P, Uguccioni M, Bordoli L, et al. CCR5 is characteristic ofTh1 lymphocytes. Nature 1998; 391:344–5.

346. Sallusto F, Lenig D, Mackay CR, et al. Flexible programs of chemokinereceptor expression on human polarized T helper 1 and 2 lympho-cytes. J Exp Med 1998; 187:875–83.

347. Qin S, Rottman JB, Myers P, et al. The chemokine receptors CXCR3and CCR5 mark subsets of T cells associated with certain inflam-matory reactions. J Clin Invest 1998; 101:746–54.

348. Zhu T, Mo H, Wang N, et al. Genotypic and phenotypic character-ization of HIV-1 patients with primary infection. Science 1993; 261:1179–81.

349. Feng Y, Broder CC, Kennedy PE, et al. HIV-1 entry cofactor: func-tional cDNA cloning of a seven-transmembrane, G protein-coupledreceptor. Science 1996; 272:872–7.

350. Villette JM, Bourin P, Doinel C, et al. Circadian variations in plasmalevels of hypophyseal, adrenocortical and testicular hormones in meninfected with human immunodeficiency virus. J Clin Endocrinol Me-tab 1990; 70:572–7.

351. Grinspoon S, Corcoran C, Lee K, et al. Loss of lean body and musclemass correlates with androgen levels in hypogonadal men with ac-quired immunodeficiency syndrome and wasting. J Clin EndocrinolMetab 1996; 81:4051–8.

352. Grinspoon S, Corcoran C, Miller K, et al. Body composition andendocrine function in women with acquired immunodeficiency syn-drome wasting [published erratum in: J Clin Endocrinol Metab1997; 82(10):3360]. J Clin Endocrinol Metab 1997; 82:1332–7.

353. Christeff N, Lortholary O, Casassus P, et al. Relationship between sexsteroid hormone levels and CD4 lymphocytes in HIV infected men.Exp Clin Endocrinol Diabetes 1996; 104:130–6.

354. Christeff N, Gherbi N, Mammes O, et al. Serum cortisol and DHEAconcentrations during HIV infection. Psychoneuroendocrinology1997; 22(Suppl 1):S11–8.

355. Jacobson MA, Fusaro RE, Galmarini M, et al. Decreased serum de-hydroepiandrosterone is associated with an increased progression ofhuman immunodeficiency virus infection in men with CD4 cellcounts of 200–499. J Infect Dis 1991; 164:864–8.

356. Mulder JW, Frissen PH, Krijnen P, et al. Dehydroepiandrosterone aspredictor for progression to AIDS in asymptomatic human immu-nodeficiency virus–infected men. J Infect Dis 1992; 165:413–8.

357. Verges B, Chavanet P, Desgres J, et al. Adrenal function in HIV infectedpatients. Acta Endocrinol 1989; 121:633–7.

358. Clerici M, Trabattoni D, Piconi S, et al. A possible role for the cortisol/anticortisols imbalance in the progression of human immunodefi-ciency virus. Psychoneuroendocrinology 1997; 22(Suppl 1):S27–31.

359. Vigano A, Principi N, Villa ML, et al. Immunologic characterizationof children vertically infected with human immunodeficiency virus,with slow or rapid disease progression. J Pediatr 1995; 126:368–74.

360. Vigano A, Principi N, Crupi L, et al. Elevation of IgE in HIV-infectedchildren and its correlation with the progression of disease. J AllergyClin Immunol 1995; 95:627–32.

361. Kovacs JA, Vogel S, Albert JM, et al. Controlled trial of interleukin-2 infusions in patients infected with the human immunodeficiencyvirus. N Engl J Med 1996; 335:1350–6.

362. Bartlett JA, Berend C, Petroni GR, et al. Coadministration of zido-vudine and interleukin-2 increases absolute CD4 cells in subjects withWalter Reed stage 2 human immunodeficiency virus infection: resultsof ACTG protocol 042. J Infect Dis 1998; 178:1170–3.

363. Carr A, Emery S, Lloyd A, et al. Outpatient continuous intravenousinterleukin-2 or subcutaneous, polyethylene glycol–modified inter-leukin-2 in human immunodeficiency virus–infected patients: a ran-domized, controlled, multicenter study. Australian IL-2 Study Group.J Infect Dis 1998; 178:992–9.

364. Levy Y, Capitant C, Houhou S, et al. Comparison of subcutaneousand intravenous interleukin-2 in asymptomatic HIV-1 infection: arandomised controlled trial. ANRS 048 Study Group. Lancet 1999;353:1923–9.

365. Davey RT Jr, Chaitt DG, Piscitelli SC, et al. Subcutaneous adminis-tration of interleukin-2 in human immunodeficiency virus type 1–infected persons. J Infect Dis 1997; 175:781–9.

366. De Paoli P, Zanussi S, Simonelli C, et al. Effects of subcutaneousinterleukin-2 therapy on CD4 subsets and in vitro cytokine produc-tion in HIV1 subjects. J Clin Invest 1997; 100:2737–43.

367. Khatri VP, Fehniger TA, Baiocchi RA, et al. Ultra low dose interleukin-2 therapy promotes a type 1 cytokine profile in vivo in patients withAIDS and AIDS-associated malignancies. J Clin Invest 1998; 101:1373–8.

368. Norbiato G, Bevilacqua M, Vago T, et al. Glucocorticoids and theimmune function in the human immunodeficiency virus infection: astudy in hypercortisolemic and cortisol-resistant patients. J Clin En-docrinol Metab 1997; 82:3260–3.

369. Norbiato G, Bevilacqua M, Vago T, et al. Glucocorticoids and inter-feron-alpha in the acquired immunodeficiency syndrome. J Clin En-docrinol Metab 1996; 81:2601–6.

370. Gett AV, Hodgkin PD. Cell division regulates the T cell cytokine

Dow




repertoire, revealing a mechanism underlying immune class regula-tion. Proc Natl Acad Sci USA 1998; 95:9488–93.

371. Hoft DF, Kemp EB, Marinaro M, et al. A double-blind, placebo-controlled study of Mycobacterium-specific human immune responsesinduced by intradermal bacille Calmette-Guerin vaccination. J LabClin Med 1999; 134:244–52.

372. Ravn P, Boesen H, Pedersen BK, et al. Human T cell responses inducedby vaccination with Mycobacterium bovis bacillus Calmette-Guerin. JImmunol 1997; 158:1949–55.

373. Miller MA, Skeen MJ, Ziegler HK. Nonviable bacterial antigens ad-ministered with IL-12 generate antigen-specific T cell responses andprotective immunity against Listeria monocytogenes. J Immunol1995; 155:4817–28.

374. Mountford AP, Anderson S, Wilson RA. Induction of Th1 cell-me-diated protective immunity to Schistosoma mansoni by co-adminis-tration of larval antigens and IL-12 as an adjuvant. J Immunol1996; 156:4739–45.

375. Chow YH, Chiang BL, Lee YL, et al. Development of Th1 and Th2populations and the nature of immune responses to hepatitis B virusDNA vaccines can be modulated by codelivery of various cytokinegenes. J Immunol 1998; 160:1320–9.

376. Ishii KJ, Weiss WR, Ichino M, et al. Activity and safety of DNAplasmids encoding IL-4 and IFN gamma. Gene Therapy 1999; 6:237–44.

377. Okada E, Sasaki S, Ishii N, et al. Intranasal immunization of a DNAvaccine with IL-12- and granulocyte-macrophage colony-stimulatingfactor (GM-CSF)-expressing plasmids in liposomes induces strongmucosal and cell-mediated immune responses against HIV-1 antigens.J Immunol 1997; 159:3638–47.

378. Kim JJ, Trivedi NN, Nottingham LK, et al. Modulation of amplitudeand direction of in vivo immune responses by co-administration ofcytokine gene expression cassettes with DNA immunogens. Eur JImmunol 1998; 28:1089–103.

379. Klinman DM, Yamshchikov G, Ishigatsubo Y. Contribution of CpGmotifs to the immunogenicity of DNA vaccines. J Immunol 1997;158:3635–9.

380. Sin JI, Kim JJ, Boyer JD, et al. In vivo modulation of vaccine-inducedimmune responses toward a Th1 phenotype increases potency andvaccine effectiveness in a herpes simplex virus type 2 mouse model.J Virol 1999; 73:501–9.

381. Asakura Y, Liu LJ, Shono N, et al. Th1-biased immune responsesinduced by DNA-based immunizations are mediated via action onprofessional antigen-presenting cells to up-regulate IL-12 production.Clin Exp Immunol 2000; 119:130–9.

382. Cenci E, Romani L, Vecchiarelli A, et al. T cell subsets and IFN-gamma production in resistance to systemic candidosis in immunizedmice. J Immunol 1990; 144:4333–9.

383. Sharma DP, Ramsay AJ, Maguire DJ, et al. Interleukin-4 mediatesdown regulation of antiviral cytokine expression and cytotoxic T-lymphocyte responses and exacerbates vaccinia virus infection in vivo.J Virol 1996; 70:7103–7.

384. Li X, Sambhara S, Li CX, et al. Protection against respiratory syncytialvirus infection by DNA immunization. J Exp Med 1998; 188:681–8.

385. Cardenas-Freytag L, Cheng E, Mayeux P, et al. Effectiveness of avaccine composed of heat-killed Candida albicans and a novel mucosaladjuvant, LT(R192G), against systemic candidiasis. Infect Immun1999; 67:826–33.

386. Cheers C, Janas M, Ramsay A, et al. Use of recombinant viruses todeliver cytokines influencing the course of experimental bacterial in-fection. Immunol Cell Biol 1999; 77:324–30.

387. Laditan AA. Hormonal profiles in children with progressively wors-ening nutritional status. Hum Nutr Clin Nutr 1982; 36C:81–6.

388. Sirinathsinghji DJ, Mills IH. Concentration patterns of plasma de-hydroepiandrosterone, delta 5-androstenediol and their sulphates, tes-tosterone and cortisol in normal healthy women and in women withanorexia nervosa. Acta Endocrinol 1985; 108:255–60.

389. Fichter MM, Pirke KM, Holsboer F. Weight loss causes neuroendo-crine disturbances: experimental study in healthy starving subjects.Psychiatry Res 1986; 17:61–72.

390. Fraser DA, Thoen J, Reseland JE, et al. Decreased CD41 lymphocyteactivation and increased interleukin-4 production in peripheral bloodof rheumatoid arthritis patients after acute starvation. Clin Rheumatol1999; 18:394–401.

391. Drott C, Svaninger G, Lundholm K. Increased urinary excretion ofcortisol and catecholami-NES in malnourished cancer patients. AnnSurg 1988; 208:645–50.

392. Goto S, Sato M, Kaneko R, et al. Analysis of Th1 and Th2 cytokineproduction by peripheral blood mononuclear cells as a parameter ofimmunological dysfunction in advanced cancer patients. Cancer Im-munol Immunother 1999; 48:435–42.

393. Sablotzki A, Ebel H, Muhling J, et al. Dysregulation of immune re-sponse following neurosurgical operations. Acta Anaesthesiol Scand2000; 44:82–7.

394. Thomas JA, Marks BH. Plasma norepinephrine in congestive heartfailure. Am J Cardiol 1978; 41:233–43.

395. Cohn JN, Levine TB, Olivari MT, et al. Plasma norepinephrine as aguide to prognosis in patients with chronic congestive heart failure.N Engl J Med 1984; 311:819–23.

396. Francis GS, Goldsmith SR, Pierpont G, et al. Free and conjugatedplasma catecholamines in patients with congestive heart failure. J LabClin Med 1984; 103:393–8.

397. Hofford JM, Milakofsky L, Vogel WH, et al. The nutritional statusin advanced emphysema associated with chronic bronchitis. A studyof amino acid and catecholamine levels. Am Rev Resp Dis 1990; 141:902–8.

398. Tage-Jensen U, Henriksen JH, Christensen E, et al. Plasma catecho-lamine level and portal venous pressure as guides to prognosis inpatients with cirrhosis. J Hepatol 1988; 6:350–8.

399. Jeevanandam M, Ali RH, Young DH, et al. Effect of nutritional therapyon polyamine metabolism in severely traumatized patients. Nutrition1991; 7:39–44.

400. Woolf PD, McDonald JV, Feliciano DV, et al. The catecholamineresponse to multisystem trauma. Arch Surg 1992; 127:899–903.

401. Brune IB, Wilke W, Hensler T, et al. Downregulation of T helper type1 immune response and altered pro-inflammatory and anti-inflam-matory T cell cytokine balance following conventional but not la-paroscopic surgery. Am J Surg 1999; 177:55–60.

402. Decker D, Schondorf M, Bidlingmaier F, et al. Surgical stress inducesa shift in the type-1/type-2 T-helper cell balance, suggesting down-regulation of cell-mediated and up-regulation of antibody-mediatedimmunity commensurate to the trauma. Surgery 1996; 119:316–25.

403. Takagi K, Yamamori H, Toyoda Y, et al. Modulating effects of thefeeding route on stress response and endotoxin translocation in se-verely stressed patients receiving thoracic esophagectomy. Nutrition2000; 16:355–60.

404. Rosenberg SA, Lotze MT, Muul LM, et al. A progress report on thetreatment of 157 patients with advanced cancer using lymphokine-activated killer cells and interleukin-2 or high-dose interleukin-2alone. N Engl J Med 1987; 316:889–97.

405. Leonard JP, Sherman ML, Fisher GL, et al. Effects of single-doseinterleukin-12 exposure on interleukin-12-associated toxicity and in-terferon-gamma production. Blood 1997; 90:2541–8.

406. Johnson B, Bekker LG, Ress S, et al. Recombinant interleukin 2 ad-junctive therapy in multidrug-resistant tuberculosis. Novartis Foun-dation Symposium 1998; 217:99–106 [discussion, 106–11].

407. Zeuzem S, Hopf U, Carreno V, et al. A phase I/II study of recombinanthuman interleukin-12 in patients with chronic hepatitis C. Hepatology1999; 29:1280–7.

408. Carreno V, Zeuzem S, Hopf U, et al. A phase I/II study of recombinanthuman interleukin-12 in patients with chronic hepatitis B. J Hepatol2000; 32:317–24.

409. Chernoff AE, Granowitz EV, Shapiro L, et al. A randomized, controlled

Dow




trial of IL-10 in humans. Inhibition of inflammatory cytokine pro-duction and immune responses. J Immunol 1995; 154:5492–9.

410. Fuchs AC, Granowitz EV, Shapiro L, et al. Clinical, hematologic, andimmunologic effects of interleukin-10 in humans. J Clin Immunol1996; 16:291–303.

411. Radwanski E, Chakraborty A, Van Wart S, et al. Pharmacokineticsand leukocyte responses of recombinant human interleukin-10. Phar-maceutical Research 1998; 15:1895–901.

412. Asadullah K, Docke WD, Ebeling M, et al. Interleukin 10 treatmentof psoriasis: clinical results of a phase 2 trial. Arch Dermatol 1999;135:187–92.

413. Wissing KM, Morelon E, Legendre C, et al. A pilot trial of recombinanthuman interleukin-10 in kidney transplant recipients receiving OKT3induction therapy. Transplantation 1997; 64:999–1006.

414. van Deventer SJ, Elson CO, Fedorak RN. Multiple doses of intra-venous interleukin 10 in steroid-refractory Crohn’s disease. Crohn’sDisease Study Group. Gastroenterology 1997; 113:383–9.

415. Borish LC, Nelson HS, Lanz MJ, et al. Interleukin-4 receptor in mod-erate atopic asthma. A phase I/II randomized, placebo-controlled trial.Am J Respir Crit Care Med 1999; 160:1816–23.

416. van Slooten ML, Storm G, Zoephel A, et al. Liposomes containinginterferon-gamma as adjuvant in tumor cell vaccines. PharmaceuticalResearch 2000; 17:42–8.

417. Kedar E, Gur H, Babai I, et al. Delivery of cytokines by liposomes:hematopoietic and immunomodulatory activity of interleukin-2 en-capsulated in conventional liposomes and in long-circulating lipo-somes. J Immunother 2000; 23:131–45.

Dow



Type 1/Type 2 Immunity in Infectious Diseases - Clinical Infectious

Documents

Transcript of Type 1/Type 2 Immunity in Infectious Diseases - Clinical Infectious