Chapter 16

Immunological Tolerance

ContentsContentsPartPart IntroductionⅠ IntroductionⅠ

Part Mechanisms of Self Tolerance ⅡPart Mechanisms of Self Tolerance Ⅱ PartPart Factors affecting Ⅲ Factors affecting Ⅲ Induced ToleranceInduced Tolerance Part Clinical Significance of ⅣPart Clinical Significance of Ⅳ Immunological Immunological ToleranceTolerance

• Owen first observed immunological tolerance to allogenic antigen in fetal period in 1945

Part IntroductionⅠPart IntroductionⅠ

AA BB• Graft of Skin

From A to B or From B to A ----No rejection

cattle of dizygotic twin

Experiment of Medawar on immunological tolerance

Definition: A type of specific unresponsiveness to an antigen

induced by the exposure of specific lymphocytes to that antigen,

but response to other antigens normally.

• Tolerogens: antigens that induce tolerance

• Types: self-tolerance

induced tolerance

Immunological tolerance

General features of immunological tolerance

• Tolerance is antigenic specific and results from the recognition of antigens by specific lymphocytes.

• Normal individuals are tolerant of their own antigens(self antigen)----- Self-tolerance.

• Foreign antigens may be administered in ways that preferentially inhibit immune response by inducing tolerance in specific lymphocytes---antigen induction.

Immunologic features of toleranceImmunologic features of tolerance

It is an antigen-induced, active process Like immunologic memory, it is antigen

specific It can exist in B cells, T cells or both

• Tolerance in T cell is longer lasting than B cell.

It is an antigen-induced, active process Like immunologic memory, it is antigen

specific It can exist in B cells, T cells or both

• Tolerance in T cell is longer lasting than B cell.

Tolerance in T and B cellsTolerance in T and B cells

Difference of Immuologic tolerance & immunodeficiency, immunosuppression

Immunodeficiency:Deficiency in the production of humoral and /or cell-mediated immunity---non-specificity to Ag

Immunosuppression: Suppression of immune responses to antigens. This can be achieved by various means, including physical, chemical----non-specificity to Ag

Part Part II Mechanism of II Mechanism of Self ToleranceSelf Tolerance

1. Central tolerance: Central tolerance occurs in the central lymphoid

organs as a consequence of immature self-reactive lymphocytes recognizing ubiquitous self-antigen.

2. Peripheral tolerance: tolerance was induced in peripheral organs as a

result of mature self-reactive lymphocytes encountering tissue-specific self antigens under particular conditions

1. Central tolerance

Clonal deletion (apoptotic cell death)

During maturation of T lymphocytes in the thymus or B lymphocytes in the bone marrow, immature lymphocytes that recognize ubiquitous self-antigen with high affinity are deleted by negative selection

Clonal deletion:negative selection of T cells in the thymus

Clonal deletion:negative selection of T cells in the thymus

Clonal Selection of T cells in the Thymus

Negative selection of B cells inbone marrow

Negative selection of B cells inbone marrow

Clonal deletion of B cells in the bone marrow

Stem cell(in red bone marrow)

B cells

BCRs

Cell with autoantigens

Cell with autoantigens

Apoptosis

Blood vessel To spleen

2. Peripheral tolerance1)Peripheral tolerance of T cells① Clonal anergy

functional inactivation without cell death: lack of co-stimulatory signal

②clonal ignorance:self-reactive lymphocytes remain viable and functional but do

not react to the self antigens in any detectable way.

Clonal anergy Clonal anergy Clonal ignorance Clonal ignorance

③ Regulatory T cells CD4+CD25+Foxp3+ Treg: TGF- , IL-10

④ AICD( activation-induced cell death) Repeated stimulation of lymphocytes by persistent antigens results in death of the activated cells by a process of apoptosis. --- FasL on activated T cell binds to Fas on activated T cell and then induces T cell apoptosis.

⑤ Immunologically privileged sites

Anatomic Barrier Immunological Suppression: TGF- , IL-10

2) Peripheral tolerance of B cells

Clonal deletion :AICD

Lack of Th cell help : Th cell anergy

Clonal anergy : express insensitive mIg

lack costimulatory molecules

Receptor editing : from self-reactive B cell clone to foreign

antigen-reactive B cell lone

Part III Factors affecting tolerance induction

1. Role of antigen

2. Role of the host

1.Role of antigens

(1)Types of antigen• Large, aggregated, complex molecules, properly processed-immune

response• soluble, aggregate-free, simple small molecules, not processed-tolerance(2)Dosage of antigen• Optical dosage-immune response• Very high or very low-tolerance(3)Portal of entry• Subcutaneous or intramuscular-immune response• Oral or intravenous-tolerance Tolerance:Oral >Intravenous>Intraperitoneal>Intramuscular>subcutaneous

(4) features of determinant

Low-zone tolerance high-zone

tolerance

Con

cent

ratio

n of

an

tibod

y

Concentration of antigen

T cells T 、 B cell

TD-Ag TD-Ag

TI-Ag

Immune response

2.Role of the host(1)Ages• Adult, immunologically mature---Immune response• Embryo and newborn , immunologically immature---

immunological tolerance(2) Differentiation state of cells• Fully differentiated; memory T & B cells—Immune

response• Relative undifferentiated B cell with only IgM, T cells

in the thymic cortex---immunological tolerance(3) Species,Heredity, Gender, Health

Host age and antigen dose affect tolerance

Host age and antigen dose affect tolerance

newborn adult

Part Clinical Significance of ⅣPart Clinical Significance of Ⅳimmunological toleranceimmunological tolerance

• Prevent the rejection of organ allografts and xenografts

• Treat autoimmune diseases

• Treat allergic diseases

1. To induce immunological tolerance

2. To terminate immunological tolerance

• To treat tumor:

enhance first signal or second signal

• To treat infection diseases

SummarySummary Definition of immunological tolerance

Features of immunological tolerance

Induction of immunological tolerance

Mechanism of immunological tolerance

Clinical application of immunological tolerance