[CANCER RESEARCH 26 Part 1, 1211-1220,June 1966]

The Destructive Effect of Radiation on Lymphatic Tissue1

CHARLES C CONGDON

Biology Division, Oak Ridge National Laboratory, Oak Ridge, Tennessee

Contents

SummaryIntroductionStudies on Destruction and Regeneration

1. General Review2. Biochemistry3. Physical Factors4. Biologic Factors5. Other Tissue Changes

Radiation PotentiationDiscussion

Summary

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The destructive effect of radiation on lymphatic tissues isinfluenced in variable ways and to different extents dependingon the physical factors concerned with the radiation itself andon biologic factors concerning the exposed organism. In thiscontext the major physical factor is radiation dose and the majorbiologic factor is local versus whole-body exposure. Presence ofnon-neoplastic pathologic changes in lymphatic tissue couldconceivably also alter radiation effects as well as the subsequentability of the lymphatic tissues to regenerate. Regeneration in theexposed tissue is interesting from the normal physiology point ofview, and the observation that granulopoiesis usually precedesreaccumulation of lymphocytes requires further consideration.

Potentiation of radiation effects by graft-versus-host and graft-versus-tumor reactions is of great interest because clinical trialsutilizing immunotherapy of cancer as a supplement to standardtherapeutic measures are now worth serious consideration. Theidea that tumor cells of lymphatic tissue origin might cause graft-versus-host reactions could form the basis for additional experiments.

It is proposed that the organ system made up of lymphatictissues be given the status of an organized academic branch ofbiomédicalknowledge in order that basic and applied research inthe field can follow some nonrandom scheme of development.

Introduction

Ionizing radiation has a profoundly destructive effect on normal lymphatic tissues in all mammalian species examined (27).Since radiation has the same destructive effects on the cells ofHodgkin's disease and of most tumors that originate in lymphatic

tissue, radiation therapy for these neoplasms is an importantpart of the treatment program.

1Sponsored by the U. S. Atomic Energy Commission undercontract with the Union Carbide Corporation.

In discussing the mechanism of radiation destruction of normallymphatic tissue, it is convenient to consider the variables involved under the 2 categories of physical and biologic factors.The physical factors refer to type of radiation, its quality andlinear energy transfer, integral dose, dose rate, and similar parameters, whereas biologic factors are those of anatomic site, age,sex, hormonal condition, nutritional status, and related aspectsof the irradiated organism or tissue. Regeneration after radiationinjury also has several features of interest for this conference.

Radiation effects on lymphatic tissues overgrown by tumorcells of Hodgkin's disease are taken up in other papers presented

at this meeting. It seems worthwhile, however, in the presentreport to mention radiation effects on some non-neoplastic pathologic or quasi-pathologic processes occurring in lymphoidorgans, because these tissue changes could play a role in thepathogenesis of Hodgkin's disease or possibly have some effect

on the outcome of therapy for the disease. I have in mind hereinflammation, progressive tissue changes, circulatory disturbances (e.g., oxygénation),graft-versus-host reactions and responses to antigenic materials, and probably the general panorama of retrogressive changes other than simple necrosis.Presumably one could also, to be complete, take up the problemof radiation effects on lymphatic tissues that have experienceddisturbances in development, now that gnotobiology and neonatal thymectomy have revealed hypoplasia of lymphoid organsin appropriate experimental circumstances.

Radiation effects on lymphatic tissues during the early stagesof an immune response or during the remarkable proliferativephase of a graft-versus-host reaction should be of special interestaccording to the view to be presented later that the histologiefeatures of Hodgkin's disease resemble a malignant immune

reaction in the same general sense that Nicholson (42) thoughtskin cancer could be referred to as "malignant skin." This pointof view about Hodgkin's disease has, as its consequence, the

additional ideas that it is a disease of the germinal centers oforganized lymphatic tissue and that either some antigenic stimulus is likely to be a continuing feature in its etiology, pathogenesis, and growth; or the opposite point of view, that some intrinsicchange in the information mechanisms of the germinal centershas occurred in such a fashion that the cells behave as thoughthey were experiencing antigenic stimuli or were unable to inactivate an antigenic stimulus.

Another matter of importance to the physician concerned withtreatment of Hodgkin's disease is the potentiation of chemo-

therapeutic agents by radiation. Radiation potentiation ofchemical injury in normal lymphatic tissue has received verylittle attention, but special interest is attached to the use ofradiation in setting up graft-versus-host immune reactions inwhich massive destruction of normal lymphatic tissue occurs.

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Studies on Destruction and Regeneration

1. General Review

Organized lymphatic tissue and individual lymphocytes areextremely radiosensitive. This finding was reported within afew years after the invention of the X-ray machine. Dunlap(24) has reviewed the extensive literature on the subject thatappeared between 1903 and the time of his paper in 1942 [seealso Engeset (27)]. Subsequently, intensive restudy of the morphologic effects of external whole-body radiation and internalemitters on lymphatic tissues was carried out during the wartimedevelopment of atomic weapons. A detailed account, with manyillustrations, of this work by R. G. Murray (41) and by P. P.H. de Bruyn (22) can be found in the Plutonium Project Recordvolume on Ilistopathology of Irradiation From External and Internal Sources edited by William Bloom (1948). Later reviews(4, 7) of radiation effects on the lymphatic tissue system refer toMurray and de Bruyn as standard descriptive works in this field.

The striking effect of a single 950 r whole-body exposure inreducing the size of normal lymph nodes in mice is shown inChart 1. Histologie appearance of an irradiated node at 3 days,after the products of necrosis have been removed, is illustratedin Fig. 1. The effect of the large acute exposure to ionizing radiation is to destroy the parenchyma of the lymph node, leaving intact the stroma, blood vessels, mature plasma cells, and retículo-

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CHAUT1.—Weightchanges in 4 peripheral lymph nodes in miceexposed to supralethal whole-body X-rays. Also shown are theweight changes in lymph nodes in mice similarly irradiated butgiven isologous bone marrow afterwards. The temporary weightincrease between 5 and 10 days after treatment was caused byextramedullary granulopoiesis. Each -point usually represents 5

endothelial (phagocytic) cells. The parenchyma refers to thecortical masses of tissue lymphocytes and the dividing cells in thegerminal centers. A few lymphocytes usually remain scatteredthrough the cortex, and stremai cores of the germinal centers aresometimes present in the tissue sections. The other organizedlymphatic tissue in the spleen white pulp, Peyer's patch, tonsil,

and thymus show the same picture of degeneration followingirradiation.

Regeneration is an intriguing matter in lymphatic tissue because the order of reappearance of parenchymal elements usuallyfollows that of the original development of lymphatic tissuesduring fetal and neonatal life, with collections of cortical lymphocytes being seen first, followed by germinal centers; thegerminal center apparently first appears during development,during regeneration after radiation, or under any other circumstances as a result of adventitious or planned antigenic stimulus(Chart 1 and Fig. 2).

There is some evidence that functional regeneration of thelymphoid system after irradiation in the adult mouse dependson the presence of an intact thymus (21). The effect of an intactthymus on regeneration of malignant lymphatic tissue afterirradiation has apparently not been studied.

The possibility that temporary extramedullary myelopoiesisin lymphatic tissues preceding their regeneration has some fundamental role in the regeneration process needs careful consideration. Presence of granulocyte-forming tissue in lymph nodes priorto regeneration or abortive regeneration has been particularlynoted in bone marrow transplantation studies (Chart 1). It hasalso been observed in spontaneous regeneration (22).

In regenerating nontumor-bearing lymphatic tissues it is unlikely that any counterpart of regeneration of the radiation-treated tumor cells of Hodgkin's disease exists. The reason forthis is the short-lived nature of the dissociated growth of germinalcenter cells in the normal immune response (12). Regeneration ofan injured dissociated growth process is not easy to conceive of,and in the present report Hodgkin's disease is interpreted to be a

malignant counterpart of the dissociated growth of germinalcenter cells in the same manner as giant follicular lymphoma isat least superficially the malignant counterpart of the hyper-plastic restitution of germinal centers that is seen a few days afterimmunization (8, 14, 32, 56). These tumor processes in lymphnodes are looked upon as "true" maturation arrests or a kind of

imago. Plasma cell tumors and multiple myeloma have as theirnormal counterpart the optional plasmablast and plasma celldevelopment that occurs after immunization with some antigens.I am inclined to consider all or nearly all primary tumors oflymphatic tissues as tumors of the germinal center or its cellularprecursors, or its cellular descendants. Spread of these tumors isnot infiltration or metastasis in the ordinary fashion becausegrowth of the normal germinal center cells is expansive, infiltrating, and shows evidence of spread to distant sites, with probablya preference for other lymphatic tissues.

During regeneration of lymph nodes after whole-body irradiation, a process that might be called "acute lymph node tumor"

has been seen infrequently (10) that is quite analogous to thephenomenon of acute splenic tumor (33, 44, 45). Presumablysome adventitious (bacterial) antigenic stimulus has caused the"acute lymph node tumor" as an expression of the immune

response in regenerating lymphatic tissue.

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Effect of Radiation on Lymphatic Tissue

There are still other morphologic phenomena in irradiatetilymphatic tissue that help complete the catalog of tissue changesthat might be considered in a conference on Hodgkin's disease.

One of these is fibrinoid necrosis in foreign bone marrow radiation chimeras. There are deposits of eosinophilic material inspleen white pulp that social stains show are composed offibrin, not amyloid (Fig. 3). Deposits of similar morphology canalso be seen more rarely in lymph node and bone marrow. Becausethe donor blood-forming cells around these deposits are destroyedor lysed, the fibrinoid necrosis is interpreted to be a manifestationof local recovery of the host immune mechanism in the radiationchimera.2

In lymph nodes or spleen, giant cell formation and reticulo-endothelial proliferation also seem to be an expression of a focalrecovery of the host immune mechanism with destruction of theforeign bone marrow graft in that particular region of the spleenor lymph node. An exaggerated expression of this process can beseen in the foreign bone marrow transplant experiment and isknown as the "micllethal dose effect" (15, 54).

The last tissue reaction that requires special consideration inirradiated lymphatic tissue is the graft-versus-host reaction (12).When certain foreign bone marrow or lymphatic tissues are givento supralethally irradiated mice, a marked temporary enlargement of the damaged lymphatic tissues appears, followed by asecondary atrophy with the sudden cessation of the proliferativephase of the graft-versus-host reaction (Fig. 4). Very similarcellular proliferation can be produced in intact animals underthe proper experimental circumstances (30), and immunologietolerance in newborn animals is presumably induced by cellularproliferation of the same type (3).

The proliferative phase of the graft-versus-host reaction has arather strong resemblance to dissociated growth of germinalcenter cells in the immunized intact animal, and both processesin turn resemble Hodgkin's disease histologically, with the exception that proliferation is only of a few days' duration in the 2

non-neoplastic conditions (Fig. 5).Snell and Stevens (49) have suggested that a tumor derived

from lymphatic tissue might be able to produce a graft-versus-host reaction, but this idea has not been developed further. Itseems unlikely that any graft-versus-host reactions are involvedin the ordinary transplantable lymphosarcomas of mice. It alsoseems unlikely that Hodgkin's disease itself is a graft-versus-

host type reaction, although this point might get further attention.

One transplantable tumor that gave a superficial resemblanceto graft-versus-host reaction in the host was seen in guinea pigscam-ing a radiation-induced acute fulminating leukemia (36).

There was extreme lymph node involvement (Fig. 6).The possibility of graft-versus-host reactions being caused by

transplantable tumors needs further evaluation with technicsdeveloped by Billingham, Brent, Medewar, and others.

In the preceding paragraphs destruction and regeneration oflymphatic tissues has been considered only in the context ofwhole-body exposure. Engeset (27) has reported comparison of

2For a more complicated story of progressive generalizedamyloidosis in radiation chimeras see the paper of Bradbury andMicklem (5).

lymph node reactions after whole-body and local irradiation. Hefound that the primary necrosis after 3000 r local irradiation isrecovered from within a few hr and that for several days theirradiated lymph node appears nearly normal except for the lossof mast cells. In the ensuing weeks, however, an extreme secondary atrophy, apparently following vascular damage, developswith destruction of the lymph node and its original stroma. Afterwhole-body exposure to much smaller doses, prolonged atrophyfrom the primary necrosis has been seen by many investigators.

Prompt temporary recovery after local irradiation has beeninterpreted to mean influx of normal cells from shielded lymphatic tissue, whereas with whole-body exposure there are nonormal cells to migrate into the atrophie tissue. This explanationseems quite reasonable because rather spectacular regeneration oflymphatic tissues takes place within a few hours in total-body-irradiated mice when they receive an i.v. injection of lymphatictissue cells (17).

3. Biochemistry

The biochemistry of necrosis has not been studied to the sameextent as the morphology of necrosis; therefore there is no firmlyestablished biochemistry of radiation necrosis in lymphatic tissues or any other organ system.

Bacq and Alexander (1) consider interruption of energy supplyand the enzyme-release hypothesis as 2 main theories of thenature of the early biochemical lesion for effects of ionizingradiation on cells. Major biochemical consequences of radiationexposure are the interference with biosynthesis of nucleic acidsand the special phenomenon of chromosome breakage.

In connection with the enzyme-release hypothesis there is anincrease in nucleases in lymphatic tissues and other organs withina few hr after exposure, but the importance of the increase incatabolic and anabolic processes for understanding the earliestsignificant biochemical lesions is uncertain.

It is generally considered that the inhibition or delay in DNAsynthesis is the single most important biochemical change inlymphatic tissues caused by radiation because one can presumethat the ionizations are in some way affecting those portions ofthe cell genome that control DNA synthesis itself. Of all thegenetic information present in lymphatic tissue cells it seemslikely that the most fundamental genetic information concernsthe task of achieving DNA synthesis (9).

It is this area of effects on genetic sites that should be evaluatedin future studies on the mechanism of radiation injury to lymphatic tissues, since these sites have the information for initiatingDNA synthesis.

Schrek and Klrod (46) report radioresistance of lymphocytes atlow temperatures, but the unusual radiosensitivity of nondivid-ing lymphocytes at body temperature has never been explained(43). It may be that the function of these cells involves their"necrosis" and that radiation somehow triggers their usual func

tional behavior. I once speculated that they represent labilestromal cells in the lymphatic tissue whose function is to holdspace until antigenic stimulation occurs and the real actors, thegerminal center cells, take over and cany out lymphatic tissuefunction. The great mass of tissue lymphocytes convenientlydie or go away to make room. Needless to say, this idea has notcaught on and many investigators think that the tissue lympho-

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cytes are the important cells in initiating an immune responseand that the germinal center cells play a secondary role (31).

The regeneration and development sequence in lymphatictissues referred to earlier does suggest that lymphocyte collections usually precede the appearance of germinal center cells. Itisn't clear whether or not this also predicts the lymphocyte origin

of germinal center cells.

8. Physical Factors

Many physical factors could be systematically investigatedin radiation injury and regeneration after local or whole-bodyirradiation in normal lymphatic tissues. Such studies would createa wealth of new information that might be of considerable valueto the radiotherapist concerned with Hodgkin's disease. Ex

ploration of physical factors, however, has been restricted to afew variables.

There is a clear dose-response relation for lymphatic tissuedamage and repair when the radiation exposure is delivered overa short interval. An interesting finding that has received littleattention is the failure of thymus weight to decrease as expectedin the kiloroentgen range of exposure.

Vogel and Ballin (55) made the original finding in rats thatinjury (as measured by weight and histology at 24 hr) to thethymus after whole-bod}' or local irradiation between 10 and 30

kiloroentgens was less damaging than below 10 kiloroentgens,where injury was directly proportional to dose. Trowell et al.(53) confirmed the essential finding of Vogel and Ballin and,further, did not think radiation fixation of the thymus or in-activation of its autolytic enzymes could explain the paradoxicaleffect. Subsequently, Trowell (52) has investigated irradiationof the thymus in vitro and has found a similar paradoxical effect in agar cultures.

The superficial resemblance of the "Vogel-Ballin paradox" to

reversal of seedling height in maize at very high radiation exposures [Schwartz (47), Schwartz and Bay (48)] was pointed outby Trowell (52). Similarly, McGrath and Congdon (39) considered the Schwartz experiment in explaining abnormal cytologieenlargement of intestinal epithelial cells after exposure to radiation.

Schwartz points to the finding that delay in cell division increases with increasing radiation dose. If death of the cell usuallyoccurs during or after its subsequent division, then prevention ofcell division would prevent ordinary radiation necrosis. Growth(protein synthesis, etc.) of the individual cells is not stopped bythe exposure and seedling growth continues temporarily.

This interesting area of radiation biology can also be related toa concept mentioned earlier in this report: that radiation effectsthose parts of the cell that contain the information mechanismfor initiation of DNA synthesis and cell division.

New interest in the effect of dose rate of whole-body exposureon lymphatic tissues is seen in the recent reports by Courtenay(19) and Gengozian (28), who found greater repair or less damageof immunologie function when the radiation was given at a lowdose rate (1-4 r/min as compared to 29-54 r/min). Transplantation of foreign bone marrow, which was their goal, was less successful when the transplant recipients were irradiated at a lowdose rate.

Dose rates in the range from 1.1 r to 8.8 r/8-hr day were in

vestigated by Spargo et al. (50) for effect on morphologicalchanges in lymphatic tissues. In this range it often took severalmonths of whole-body exposure to produce discernible changes.

Type of radiation is an important physical factor. X-rays andgamma rays have been used more often for radiation effectstudies than other types. However, using beta rays, alpha particles, and neutrons, Murray (41) and de Bruyn (22), found thesame severity of radiation damage with the different kinds ofradiation.

Because the quality or energy of radiation as well as the linearenergy transfer (LET) varied greatly with the several types ofexposure, it is concluded that these physical factors are likelyto be associated with quantitative differences in radiation effects on lymphatic tissues rather than any qualitative alteration[see Bateman and Bond (2)]. Proton and meson effects on lymphatic tissues have apparently not been investigated.

4. Biologic Factors

Anatomic site is the major biologic factor in all radiation effects in mammals because of the remarkable variations in organsensitivity. Within the lymphatic tissue organ system, however,all sites appear to be essentially equally radiosensitive. We havenoted, though, that thymus regenerates faster than other lymphatic tissues (10, 11).

Extracorporeal irradiation of blood and lymph has been studiedby Cronkite and his colleagues (20) for its effect on normal aswell as neoplastic lymphatic tissues. This method of irradiationis interesting, not only because of the depletion of lymphocytes,but also because stem cells from the hemopoietic and lymphatictissue systems that normally circulate in the peripheral bloodare irradiated (29). Presumably their malignant counterparts,that also circulate, are also effectively irradiated, because theprocedure has shown some therapeutic effectiveness in certainleukemias.

Factors of age, sex, hormonal conditions, nutritional status,and other variables operating within the range of physiologicallynormal values are not known to influence radiation destruction oflymphatic tissues. They might play a role in regeneration, butthis point requires special investigation.

If other functional or pathologic parameters of lymphatictissue injury such as immune response and tumor induction areconsidered, then these biologic factors operating within thenormal or an exaggerated range can play a significant role in theconsequences of the radiation effect. An example of this is themajor effect of hormonal status on yield of radiation-inducedtumors of the thymus in mice (34).

5. Other Tissue Changes

In the foregoing sections consideration has been given to radiation effects on normal lymphatic tissues and their regeneration.The present section is intended to point out that radiation effects on lymphatic tissue changes other than neoplasia could beof interest in a conference on Hodgkin's disease.

Radiation effects on lymphatic tissues that have experienceddisturbances in development or show retrogressive changes havenot been systematically studied, although, as mentioned earlier,neonatal thymectomy and germfree life yield hypoplasia of the

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Effect of Radiation on Lymphatic Tissue

lymphatic tissue system. The preliminary finding in these studiesis a failure of the system to regenerate properly as measured byits immunologie function.

Congestion and other circulatory disturbances would be ofinterest to study. Considerable attention is now directed towardhyperbaric oxygen radiotherapy in cancer, and Wildermuth(57) has recently summarized work done in this field. Apparentlythe joint effects of hyperbaric oxygen and radiation on lymphatictissues have not been studied, but the use of this method forHodgkin's disease and other tumors of lymphatic tissues does not

need to await studies on normal lymphatic organs.Ionizing radiation has been used in the treatment of inflam

mation, parasitism, and chronic infective granulomas [see El-linger (26)]. Looking at the situation in another way, one canraise the question concerning the effects of radiation on lymphatic tissues when inflammation, parasitism, or granulomataare present in the tissues. Presumably radiation destruction andregeneration would be affected by the presence of these complicating tissue changes. In mice, parasites are often found in themesenteric lymph node, where they incite chronic inflammatoryprocesses that alter markedly the radiation effects in these areas.Progressive tissue changes consist of alterations like regeneration,metaplasia, and hyperplasia. How the presence of these basictissue changes would influence radiation destruction and regeneration is not known.

So far as we know, the primary function of lymphatic tissuesis immune response; and our general impression from histologiestudy is that adventitious immune reactions are nearly universally present in conventional animals (12). Radiation effects innormal lymphoid organs take place against a variable immuneresponse background.

There is an extensive literature dealing with radiation immunology [see Taliaferro et al. (51), Makinodan and Gengozian(37)] that has not been evaluated in the context of our presentconference. The findings in radiation immunology might contribute something to radiotherapy or some other aspect of Hodgkin's disease.

Meaningful ideas might develop if a phase of radiation immunology dealt with chronic antigenic stimulation rather thanthe pulsed antigen administration that is usually studied.

One rather interesting finding is that a residual immune response exists after whole-body irradiation (12, 16). Serum antibody production is prevented by exposures less than 1000 r ifthe antigen and radiation are given at about the same time.However, with certain kinds of antigens it may take 3000 r toprevent all histologie evidence of an immune response (18). Inthis sense there is a residual component of the immune responsethat is extremely radioresistant. Some of the cells involved inthe residual immune response have at least a superficial resemblance to the Reed-Sternberg cells of Hodgkin's disease, thus

contributing to the concept stated earlier that the disease is akind of malignant immune response (Fig. 7).

Radiation effects on graft-versus-host reactions in lymphatictissues could relatively easily be studied now that there has beenconsiderable recognition of their morphologic features in mice(12, 13).

Splenic amyloidosis in mice seems to have some connectionwith absence of germinal centers (J. W. Goodman and C. CCongdon, unpublished data). Radiation effects on splenic amy

loidosis probably should be examined for information whichmight contribute to our understanding of pathologic changes ingerminal centers.

Radiation Potentiation

This topic might be easiest to look at as a restricted case of themore general problem of action of multiple injurious agents onbiologic systems. Dual- or triple-action situations in biology andmedicine are notoriously difficult to work with and understand.

In the present context radiation potentiation is taken to meaninjury to normal lymphatic tissues by some agent with a potentiation of this effect by exposure to ionizing radiation. The condition in which some agent, such as increased oxygen in the radiation field, increases the radiation effect is also a facet of thepotentiation concept and is usually thought of as radiation sen-sitization.

Substances that intensify radiation effects have been studiedfor many years (40). Synkavit, a phosphoric ester of a substancerelated to vitamin K, has been examined rather extensively forits radiation-sensitizing actions, but its use in clinical medicinehas not been widely promoted [Bacq and Alexander (1), pp. 477-79]. Bacq and Alexander suggest that cells normally contain aspart of their physiologic processes radioprotective agents thatcontrol their usual radiosensitivity; radiosensitizing or radio-potentiating agents interfere with the action of these protectivesubstances.

An interesting basic approach to the problem is to take a veryradioresistant organism such as Micrococcus radiodurans anddevelop agents that increase its sensitivity (6).

Antimetabolites or any toxic chemical will make an irradiatedanimal sicker than when a single injurious agent is used, andmany antimetabolites have been examined in microorganism ortissue culture systems. A histologie evaluation in lymphatic tissues has not been made, although there is good reason to do this.Antimetabolites combined with radiation have been studied foreffects on the immune mechanism.

It was mentioned earlier that radiation effects on the thymusare increased by hormones and substances that injure the thymuswhen administered alone.

The extreme destructive effects of graft-versus-host reactionson lymphatic tissues deserve special consideration, and presumably a systematic examination of this immunologie reaction willeventually be made from the radiation potentiation point ofview (Fig. 8).

In addition, as mentioned in the discussion, immunotherapy ofcancer by means of graft-versus-host reactions is a topic thatrequires major consideration by cancer therapists.

Discussion

Even though this paper has been somewhat ambitious in scope,it still isn't a comprehensive review of radiation effects on lym

phatic tissues. Instead, my plan has been to call attention tofindings in the radiobiology of lymphatic tissues that might beof near or even remote interest to a group discussing obstacles tothe control of Hodgkin's disease.

One of the first ¡jointsto be made is that in spite of the ratherbizzare histologie pictures that Hodgkin's disease presents they

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seem to mimic the histology of normal and pathologic immunereactions in intact or irradiated lymphatic tissues. This suggestion immediately puts Hodgkin's disease into the framework of

a malignant immune reaction that cannot be turned off, whereasnormal and nonmalignant pathologic immune reactions areuniquely self-limited, at least from a histologie point of view.Either the tumor cells are driven by an unusual antigenic stimulus, or some lesion of information concerning initiation of celldivision or turning off of cell division is present.

There is a particularly interesting neoplastic lesion in the mousemesenteric lymph node that resembles Hodgkin's disease (25).

It might well be studied with the above thoughts in mind. Inaddition, the concept of Hodgkin's disease being one of the germi

nal center diseases could be looked at in the mesenteric lymphnode disease in mice.

Destruction and regeneration in lymphatic tissues require moreintensive study in relation to all of the problems outlined in thepresent text. In fact, I feel this organ system is so importantthat it deserves a kind of specialty status in the sense that hema-tology is a specialty devoted to bone marrow function. It may bethat a more systematic evaluation of the lymphatic tissue organsystem in health and disease could develop as the essential content of this speciali}- or subspecialty. At the present time the

closest thing to a field concernedprimarily withstudy of lymphatictissues is the growing area of experimental hematology. Increased interest in the biochemistry of lymphatic tissues is sorelyneeded.

Potentiation of radiation effects by graft-versus-host reactionsin lymphatic tissues is clearly possible from the extensive research on bone marrow transplantation. Clinical experiments ongraft-versus-cancer reactions have been considered or carriedout for a number of years (38). We now think immunotherapy(graft-versus-tumor) may be a good idea to attempt in Hodgkin's

disease to supplement the other forms of treatment.The principal idea is to obtain fresh tumor tissue and use it to

immunize a normal human or possibly a primate. After obtainingtissue the Hodgkin's disease patient would receive treatment to

reduce the remaining tumor mass to as low a level as feasible.At this point systemic chemotherapy would be stopped and thepatient would receive, i.V., thoracic duct lymphocytes in verylarge numbers from an immunized relative or other individual.The clinical experiment would be analogous to the immunotherapy of chemically induced sarcomas in rats reported byDelorme and Alexander (23). It is presumed that unique antigensor a virus, or both, might be present in Hodgkin's disease tumortissue, and that temporary graft-versus-tumor reactions of asecondary response type might take place and destroy theresidual tumor tissue.

The experimental demonstration of unique antigens has beenlimited so far to chemical- and virus-induced tumors in animals(35). However, nearly all tumors show disturbances in chromosomal karyotype; if this universal lesion has any connection withthe antigenic changes now found in certain induced neoplasms,then a fundamental basis for the immunotherapy of cancer isclearly foreseeable.

Even though these speculative relationships are still unevalu-ated, I think one can justify proceeding with immunotherapyexperiments in man in situations where chemotherapy or othermethods give marked reduction in tumor mass but with inevitablerecurrence of the neoplasm. There is no a priori reason for not

trying immunotherapy as outlined above in other cancer cases,with the realization that the animal experiments suggest at thistime a rather restricted cancel1situation.

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Charles C Congdon

FIG. 1. Depleted lymph node 3 days after 950 r of whole-body X-ray. Note stromal core of germinal center near marginal sinus. H

& E, X 250.Fio. 2. Regenerating lymph node 12 days after 950 r and isologous bone marrow showing large mass of lymphocytes in the cortex

and slight granulopoiesis iu the medulla. II & E, X 250.FIG. 3. Fibrinoid necrosis of the spleen white pulp 12 days after lethal whole-body irradiation and homologous bone marrow injec

tion. H & E, X 250.FIG. 4. Proliferation phase of graft-versus-host reaction in a lymph node 8 days after lethal whole-body irradiation and homologous

bone marrow injection. H & E, X 250.FIG. 5. Blurring of the white pulp in a normal mouse 2 days after an i.v. injection of sheep red blood cells. The process is also re

ferred to as disassociated growth of germinal center cells. H & E, X 120.FIG. 6. Fulminating leukemia in the lymphatic tissue of a guinea pig that was exposed to chronic whole-body gamma radiation.

There is a superficial resemblance to graft-versus-host reactions. H & E, X 340.FIG. 7. Residual immune response in spleen white pulp 2 days after 950 r of whole-body irradiation and an i.v. injection of human

saliva. Note very large cells near middle of photograph. H & E, X 375.FIG. 8. Peripheral lymph node destroyed by graft-versus-host reaction in an irradiated mouse 17 days after homologous bone mar

row transplant. H & E, X 100.

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Effect of Radiation on Lymphatic Tissue

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1966;26:1211-1220. Cancer Res   Charles C Congdon  The Destructive Effect of Radiation on Lymphatic Tissue

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