Manifestations Ofimmunologie Unresponsiveness Inhodgkin's

[CANCER RESEARCH 26 Part 1, 1152-1160,June 1966] Manifestations of Immunologie Unresponsiveness in Hodgkin's Disease1

ALAN C. AISENBERG Massachusetts General Hospital, Boston, Massachusetts

Summary the presence of active tuberculosis (36, 71). Finally, partly as a consequence of Dubin's writings (20), Schier and his colleagues The immunologie defect of early Hodgkin's disease is charac (65, 66) tested with a variety of allergens and found that tuber terized by a depression of delayed hypersensitivity and can be culin anergy in Hodgkin's disease was but 1 manifestation of a assessed by negative reactions to a battery of delayed allergens more general unresponsiveness to delayed-type antigens. or by inability to acquire contact sensitivity. While the homograft reaction is depressed in these patients, antibody formation Delayed Hypersensitivityâ€”Loss of Preexisting Sensitivity is largely intact and the lymphocyte count is normal or but slightly depressed. It is suggested that the anergy of early Delayed hypersensitivity, in contrast to the immediate, Hodgkin's disease is a peripheral defect; a manifestation of ab antibody-determined response, is mediated by cells and is normal lymphocyte function. This suggestion is supported by measurable only by skin reactivity. Tuberculin hypersensitivity preliminary work with Hodgkin's lymphocytes in vitro and fol (and other forms of bacterial hypersensitivity) and contact sensi lowing lymphocyte transfer. Later in the course of the condition tivity are the classical examples of the delayed type of response. profound lymphopenia develops and most probably contributes In studying delayed allergy, the slow evolution of the reaction to the more severe and complex immunologie deficiencies of (over a period of 24-48 or more hr) which follows the application advanced Hodgkin's disease. of the antigen is most useful in distinguishing it from antibody- mediated Arthus skin reactions. It is depression of delayed Introduction hypersensitivity which constitutes the characteristic immuno logie defect of early, active Hodgkin's disease. Understanding of the pathogenesis of Hodgkin's disease, un Thus, Schier et al. (66) reported (Table 1) that in a group of satisfactory as it is, has been both obscured and clarified by the 79 controls, 71 % responded to purified tuberculoprotein (P.P.D.), association of this condition with tuberculosis. In the past this 90% to mumps skin-test antigen, 92% to Candida albicane, and association led to confusion about the etiologic relationship of the 2 granulomatous processes, and even Sternberg's early histo 68 % to Trichophyton gypsewn. In the group of 43 patients with Hodgkin's disease the figures for the same delayed-type allergens logie description suffers from this defect (72). It was only with were 23%, 14%, 19%, and 16%, respectively. Other investi the classic monograph of Dorothy Reed (61) that the separate gators have confirmed these findings (39, 69). nature of the 2 diseases was unequivocally established. An asso ciation with Hodgkin's disease has been demonstrated for Cutaneous anergy does occur in the course of other diseases, including leukemia and carcinoma (43), but it differs from the tuberculosis (21, 36, 60), and more recently and in more strik anergy of Hodgkin's disease in appearing only late in the progress ing manner also for cryptococcosis (19, 24, 80), histoplasmosis, of these diseases when the patients are in poor condition (39, 69). and several other rare mycotic infections (28) and for herpes The Minnesota group (39) studied skin sensitivity to a group of zoster (78). (Since these infectious complications form the sub delayed allergens (diphtheria toxoid, mumps, Trichophyton, stance of a subsequent paper in this symposium they will not be Candida, and P.P.D.) in subjects with and without Hodgkin's dealt with in detail here). disease (Table 2). They found that even when in good condition, But the aforementioned association with tuberculosis also in 26 of 49 patients with Hodgkin's disease (53%) were anergic to directly brought about the recognition of the immunologie defect in Hodgkin's disease. First, the high coexistence of tubercle the entire group of allergens. On the other hand, in subjects without Hodgkin's disease who were in good condition, anergy bacillus and mycotic infection in this condition led quite natu rally to the suggestion of decreased resistance to these agents, was observed in only 3 of 208 normal controls, none of 27 pa a decrease which could be mediated through an immunologie tients with carcinoma, 3 of 25 patients with leukemia, and 1 of defect. Secondly, tuberculin testing of large numbers of Hodgkin's 20 with non-Hodgkin's lymphoma. However, when patients in poor clinical condition were studied, 7 of 8 with Hodgkin's dis patients (20, 55, 71) revealed that these individuals displayed a much higher degree of tuberculin negativity than did the control ease, 12 of 32 with carcinoma, 5 of 10 with leukemia, and 13 of population. Quite typical of the early tuberculin studies is that 21 with lymphomas other than the Hodgkin's type were anergic. of Steiner (71), who found that 29 of 33 Hodgkin's patients were Sokal and Primikirios (69) also studied a group of patients with unrcactive to 0.001 mg of human tuberculin, while the majority Hodgkin's disease, patients with lymphomas other than of his control population reacted to this concentration. Indeed, Hodgkin's type, and control subjects with other malignant and Hodgkin's patients frequently remained tuberculin negative in nonmalignant conditions using similar antigens and derived similar conclusions (Table 3). Depression of skin reactivity was 1The author's work is supported by Research Cirant CA-07179 most marked in patients with Hodgkin's disease, who were of the National Cancer Institute, USPHS. This is Publication anergic to the antigens used even when their disease was asymp 1231 of the Cancer Commission of Harvard University. tomatic. Asymptomatic patients with lymphoma other than lir.2 CANCER RESEARCH VOL. 26

TABLE 1 TABLE 4 CUTANEOUS RESPONSE (%) TO DELAYED ALLERGENS" SUMMARYOF DINITROCHLOROBENZENETESTING IN HODGKIN'S DISEASE (1) GroupControlsHodgkin's of patients7943Mumps9014Candidaalbicans9219Trichophylontypseum6816P.P.D.67123 disease15201415Active disease25400040

diseaseXo. No. ofpatientsNo. oftestsPositiveEquivocalNegative Â»Modified from Schier et al. (66). h Purified protein derivative. (anergic)Inactive

TABLE 2 COMPARISONOF THE INCIDENCE OF ANERGY AMONGPATIENTS benzene (Table 4). Those with Hodgkin's disease quiescent for IN GOOD OB POOR CONDITION" more than 2 years had normal skin reactivity, whereas patients with disease quiescent for shorter periods were either normal or CONDITIONNo. CONDITIONNo. anergic. In this study 2 patients were observed to recover skin GROUPControlIlodgkin's sensitivity with subsidence of active disease, and Sokal and tested20849272520No.anergic326 tested8 anergic7 anergic88 Primikirios (69) have likewise observed 2 patients who recovered tuberculin sensitivity after subsidence of the pathologic process. The latter workers also found that although none of 3 Hodgkin's patients with systemic manifestations became tuberculin positive CarcinomaLeukemiaNon-Hodgkin's 031%anergic1.4530125POOR321021No. 12513% 385062 after bacillus of Calmette-GuÃ©rin (BCG) vaccination, 10 of 12 individuals without such manifestations did become reactive to 2nd strength tuberculin. [Refractoriness of the Hodgkin's pa lymphomaGOOD tient to contact sensitization has been confirmed by other " Modified from Lamb et al. (39). workers with the related allergen dinitrofluorobenzene (44).]

TABLE 3 Antibody Formation and y-Globulin Levels INITIAL SKIN REACTIONSTO TUBERCULIN, TKICHOPHYTON,AND In contrast to the early loss of delayed hypersensitivity, anti CANDIDAANTIGENS" body formation appears to be relatively well preserved in Hodgkin's disease. While some workers have observed depressed P.P.D.6No.tested193029309132168%Positive0201420333844TrichophytonNo.tested161428209025151%Positive1314730181221CandidaNo.tested161428209025151%Positive67435202833antibody formation to pneumococcal polysaccharide (23, 40), DIAGNOSISHodgkin'sdiseaseLymphocyticlymphomaCancerNonneoplasticdiseaseNormal TIONS+â€”+â€”Â±Â±-INTERMEDIATE brucella (20), and primary immunization with tetanus (12), other investigators have reported series in which the majority of patients produced normal amounts of antibody to typhoid- paratyphoid (28, 34), mumps (66), tularemia (64), blood group substances (22), and secondary immunization with tetanus toxoid (12). Recently, antibody formation to Types 1 and 2 pneumococcal polysaccharide was studied in Hodgkin's patients whose anergy had been established by prior testing with dinitrochlorobenzene, and good antibody formation to both antigens controlsSYSTEMICMANIFESTA was observed in 13 of 19 patients (6). Of the 6 who failed to pro duce both antibodies, 4 were in very poor condition and died " Modified from Sokal and Primikirios (69). within 6 months of testing. The varying conclusions of different 6 Purified protein derivative. investigators on the antibody-forming ability of the Hodgkin's patient may reflect a difference in response to primary and Hodgkin's type or with other malignant and nonmalignant secondary antigenic stimulation (12), or a difference in the lesions had little depression of skin reactivity. strength of the antigenic stimulus employed (6). It also seems Delayed Hypersensitivityâ€”Active Sensitization quite likely that the general clinical state of the patient studied is of importance; i.e., in the terminal stage of Hodgkin's disease The assessment of delayed hypersensitivity by skin testing, the ability to form antibodies is lost. i.e., the studies discussed in the prior section, has the disadvan Although the preponderance of evidence indicates that the tage of being unable to distinguish the anergic person from the nonterminal Hodgkin's patient retains antibody-forming ability individual never exposed to the allergen. To circumvent this 37 in response to most antigens, a subtle defect in this function is patients with Hodgkin's disease were sensitized with the delayed- not precluded. Indeed, evidence that the duration of the anti type (contact) allergen dinitrochlorobenzene (1) by a procedure body response may not be sustained in the normal manner in which results in the almost uniform sensitization of normal Hodgkin's patients (6, 34) and the difference in response to pri persons. All 25 patients with active disease, even when the mary and secondar}' stimulation (12) suggest some defect. There process by clinical criteria was quite localized, were anergic as is a need for investigation of the quality of the antibody response evaluated by the inability to become sensitive to dinitrochloro- in Hodgkin's disease, particularly with respect to 7 S and 19 S

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antibody. Finally, it should be pointed out that technics for No. Of Coses antibody measurement are intrinsically more sensitive than those 20 used to assess delayed hypersensitivity. normal i The normal or slightly elevated 7-globulin levels that are range 15 characteristic of Hodgkin's disease (9, 49) are consistent with the ADVANCED HODGKIN'S DISEASE !50 AUTOPSIED CASES! essentially normal state of antibody formation which is observed. A recent study reports that only 2 of 69 patients were hypogammaglobulinemic (49), though it is our impression that de pressed 7-globulin levels are not uncommon in terminal cases. For example, among 19 patients recently studied, 3 of 4 with terminal disease were hypogammaglobulinemic (6). ONSET OF DISECASE !50 AUTOPS/ED CASES! Homograft Rejection The rejection of a skin homograft is probably a more complex immunologie function than either delayed hypersensitivity or antibody formation. While under most conditions the homotransplantation reaction is mediated by a cellular mechanism, it appears that, exceptionally, antibody may play a critical role ONSET OF DISEASE (8, 15, 30). Of the 29 reported skin homografts to Hodgkin's (25 OUTPATIENT CASES! patients, 17 (59%) survived 30 days or longer (32, 38, 50). There were no such abnormal skin graft survivals among 8 patients with acute or chronic myelocytic leukemia, but there were 10 survivals (30 days or more) among 23 individuals with chronic lymphatic leukemia and multiple myeloma. This latter finding makes the skin graft data in the Hodgkin's patients difficult to interpret, since the immunologie defect in lymphatic leukemia and myeloma involves antibody rather than delayed hyper sensitivity (49, 74). There is a much quoted case of the long term 0 0.5 1.0 1.5 2.5 3.5 survival of a bone marrow graft in a Hodgkin's patient which LYMPHOCYTE COUNT PER Cut mm xlO3 CHART1. Lymphocyte counts in Hodgkin's disease (5). resulted in a blood group chimera (13). the Hodgkin's disease process itself. It is worth pointing out that Lymphocyte Levels Early students of Hodgkin's disease were aware of the con the blood lymphocyte depression in this condition reflects a de pression of tissue lymphocytes (63). sistent lymphocytopenia that these patients exhibit (18, 79) Thus in 1936 Wiseman described depressed lymphocyte counts Lymphocyte Transfer Reactions in 87% of a series of 31 patients with this condition (79). The lymphocytopenia of Hodgkin's disease assumes new significance Since lymphocyte counts of the early, anergic Hodgkin's pa in the light of recent investigations on the role of the lymphocyte tient are frequently in the normal range, it is quite unlikely that in immunologie reactivity (30), in particular, evidence that the immunologie defect of these patients can be explained by cellular or delayed hypersensitivity is mediated by this cell lymphocytopenia. The logical extension of this line of reasoning (30, 41, 75). is investigation of the functional capacity of the Hodgkin's The upper part of Chart 1 illustrates the extreme lymphopenia lymphocyte, a goal which can only be imperfectly realized. This which characterizes the terminal 6 months of advanced Hodgkin's section and the following are concerned with preliminary efforts disease (5). The lymphocyte counts of only 2 of 50 patients fell in this direction. Gray and Russell (31) have recently described within the normal range. However, the lower and middle parts a lymphocyte transfer technic for screening donor/recipient of Chart 1 indicate that profound lymphopenia is not common compatibility in human homotransplantation in which purified at the onset of disease. Both in the outpatient and autopsy series, lymphocytes from the proposed recipient are transferred into the lymphocyte counts at the onset of disease tended to be either skin of the proposed donor. The test is closely modelled after a slightly depressed or within the low-normal range. Although in similar technic employed by Brent and Medawar (16, 17) in this series counts within a month of any therapy were excluded guinea pigs and in essence assumes that the reaction of the from consideration, it remains difficult to assess to what extent transferred lymphocytes is a graft versus host reaction based on lymphopenia may be a remote result of irradiation, alkyl- histocompatibility differences. ating agent, or corticosteroid therapy. In examining individual It must be pointed out before proceeding that the transfer of case records one gets the impression that it is the disease itself lymphocytes from 1 individual to another, though operationally rather than its therapy which determines lymphopenia, but it is simple, on a theoretical level represents a most complex phe extremely difficult to establish this objectively. The fact that nomenon. Immunologie reactivity in 2 directions is possible, lymphopenia was observed prior to the era of alkylating agents, either from grafted lymphocytes against host or from host corticosteroids, and extensive radiotherapy (79) also implicates against graft. Both of these reactions could be expected to be

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TABLE 5 most obvious when the Hodgkin's cells are compared with normal LYMPHOCYTETRANSFERREACTIONIN HODGKIN'S RECIPIENTS (3) lymphocytes transferred to the same individual at the same time, and is observed in l>oth immunologically normal and Hodgkin's (mm)48 recipients. Third, some of the Hodgkin's recipients in very poor RECIPIENT(Condition)HD-1 condition (Table 5) fail to show much reaction to either normal hr757G584853302days14100850 days6?40 or Hodgkin's lymphocytes during the early days (48 hr) of the (Good)*HD-2 transfer reaction. We take this 3rd abnormality to be a mani festation of much more severe (and separate) immunologie im pairment, which occurs in the far advanced patient, while the second we believe reflects a functional impairment of the early, (Good!H anergic Hodgkin's individual. Again, it should be stressed that these observations on the lymphocyte transfer reaction are open (5)0 (?5)0 to alternate interpretations. (?3)98Ãœ (?3)96008<0 In Vitro Lymphocyte Studies I) -4(Good)HD-G In an attempt to confirm a functional lymphocyte abnormality (2)0 in Hodgkin's disease, the in vitro response of these cells to various D-Ã³N-lN-2HD-1HD-3N-lHD-8INDURATION*"(2)48000211-14 stimuli has been investigated. This work was based on the ob servation that human lymphocytes undergo morphologic altera (Poor)HD-7 tion (blast transformation), deoxyribonucleic acid synthesis, and (3)2 finally cell division in response to phytohemagglutinin and mixed (3)02?47 cell culture (11, 33). It was found convenient to use the incorpo ration of a pulse of carbon-labeled thymidine into deoxyribo (Poor)DONORN-lN-2HD-2N-lN-3HD-3HD-4N-lN-2HD-3H nucleic acid as a measure of lymphocyte reactivity (4), which is arbitrarily expressed in cpm/1.25 X IO5lymphocytes (Table 7). The results, which are preliminary in nature, do suggest that the " Average diameter of induration. When erythema exceeds in lymphocytes from 7 of the 10 Hodgkin's individuals examined duration, this is noted separate!}' in parentheses; otherwise have a depressed response to 1 or both stimuli (phytohemagglu- induration and erythema are coextensive. A question mark indi tinin or mixed cell culture). Thus, the in vitro investigations cates barely perceptible induration or faint erythema. * IID, Hodgkin's disease; N, normal. tend to support the deficiency seen upon lymphocyte transfer. c Induration undimiiiished at 21 days. Discussion modified or determined by the respective histocompatibility The literature on the immunologie deficiency of Hodgkin's antigens of host and graft, and in both, reactivity residing in disease has been unnecessarily obfuscated by the frequent failure donor and host lymphoid cells at the time of transfer and that to separate other lymphoid disorders (lymphosarcoma, lymphatic developing after the delay required for sensitization must be leukemia, and even multiple myeloma) from Hodgkin's disease. considered. Finally, the strong possibility exists that at least part The deficiency of these other lymphoid disorders is strikingly of the skin reaction seen after lymphocyte transfer is not immu different from that under consideration in the present paper. nologie in nature. Despite these reservations, transfers of pe Indeed, the defect of lymphatic leukemia and multiple myeloma ripheral Ivmphocytes in Hodgkin's disease have been instructive is quite similar to that of the congenital, sex-linked form of (3). agammaglobulinemia (26, 28), being characterized by hypo- In these experiments, the Hodgkin's individual has differed gammaglobulinemia, poor antibody formation, and frequent from the normal, with greater or lesser consistency, in 3 particu bacterial infections (49, 74). (It is of interest to speculate whether lars (Tables 5 and 6). First, in some Hodgkin's recipients the immunologie status of reticulum cell sarcoma will be found (Table 5) the reaction of normal lymphocytes is abnormally pro to resemble that of Hodgkin's disease). tracted [reactions persisting at 21 days compared to the normal A 2nd point which is often neglected in immunologie investiga reaction (31), which is almost always complete by the 7th-10th tions is the disease stage of the Hodgkin's patient and his general day]. This is reasonably ascribed to delayed rejection of the condition. It is essential for understanding the immunologie grafted lymphocytes in the anergic Hodgkin's patient and may status of the Hodgkin's patient to recognize that this disease be analogous to the protracted transfer reaction seen in the cannot be considered to be an immunologie entity but is rather a guinea pig recipient that has been X-irradiated (17). Second, and clinical condition with varying involvement of the reticuloendo- for the purposes of the present argument most significant, is the thelial system. Presumably the immunologie deficiency alters depressed reactivity of transferred Hodgkin's lymphocytes and progresses with the advancing disease process. Throughout (Tables 5 and 6). This depression, which we consider to be a re the preceding presentation an attempt has been made to define flection of anergy of the lymphocyte donor (all these subjects disease involvement in relation to the immunologie studies, and were anergic as evaluated with dinitrochlorobenzene), appears Table 8 summarizes this approach. In the table Hodgkin's only 7 days and later after transfer, when the initial skin reaction disease has been divided arbitrarily into 4 divisionsâ€”healed which Hodgkin's lymphocytes may display has subsided. It is localized disease, active localized disease [Stage I or II of Peters

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TABLE 6 SUMMARYor LYMPHOCYTETRANSFERREACTIONS(3)

(mm)No.OF INDURATION

OFTRANSFERS1414933312210107222114DIAMETER DOXORNormalNormalHodgkin'sIlodgkin'sRECIPIENTNon-Hodgkin'sHodgkin'sNon-Hodgkin'sHodgkin'sTIME48ofpatients0-2217616177916143-57301011241072055102171914520630Av.diameter5.55.11.45.06.64.65.51.703.71.60

hr7 days11-14 days48

hr7 days11-14 daysNo. and Middlemiss (57)], generalized disease, and the terminal TABLE 7 condition. /.v VITKOREACTIVITY"OFNORMALAND HODGKIN'SDISEASE The immunologie deficiency of early, active (localized) disease LYMPHOCYTES(4) is characterized by loss of reactivity to delayed allergens and inability to acquire contact sensitivity. Antibody function is culture5.35.35.25.212.10.0310.310.30.030.050.055.50.250.25Tuberculin(P.P.D.)0.25 essentially intact and the blood lymphocyte level either normal or but slightly depressed, while impaired function of this cell N-lN-2N-3N-4N-5N-6N-7N-8N-9N-10HD-1HD-2HD-3HD-4HD-5HD-6HD-7HD-8HD-9HD-10Control0.030.060.200.560.220.100.140.430.040.230.590.080.120.060.000.050.010.560.250.45Phyto-hemagglutinin13017.967.528.2.55.7153.071.03153315.12.00.125.21747.011.0Mixed(+)0.24 may be reflected in the depressed reaction of transferred (-)0.60 Hodgkin's lymphocytes (Di). If through treatment or other (-)3.9 wise a prolonged period of disease inactivity (healing) occurs, the evidence suggests that normal delayed hypersensitivity is restored (1, 69). (+)4.5 In the progression to advanced (generalized) disease, it is (+)0.10 likely that the depression of delayed hypersensitivity becomes (-)0.31 more profound, though investigation of this point is elusive (-)3.7 because of the difficulty in quantitating delayed hypersensitivity Since the ability to acquire dinitrochlorobenzene sensitivity is (+)0.12 absent in the early patient, contact sensitization is not helpful (-)0.12 in determining the intensity of unresponsiveness. However, there (-)0.87 does appear to be a higher incidence of unresponsiveness to (-)0.33 delayed allergens (39, 69) in advanced Hodgkin's disease, and it (-)0.05 is in these patients that mycotic infections are usuali}- seen. The (-)0.02 (-)0.59 peripheral lymphocyte count is now moderately or severely (-)0.20 depressed (5), and evidence for abnormal lymphocyte function (-)0.55 obtained from transfer studies (3) is now supported by the (-) preliminary in vitro investigations (4). While gross antibody " Reactivity is expressed in cpm/1.25 X IO5lymphocytes. Two synthesis is still intact in such individuals, there are less obvious lie of thymidine-2-14C were added to each culture. The sign in hints of disturbed antibody formation (6, 12). parenthesis in the tuberculin column represents the status of the Although the immunologie deficit is more severe in the terminal conventional tuberculin test (0.1 ml of 1:1000 old tuberculin intra- Hodgkin's patient it is probably the least interesting because it cutaneously). is the least specific. In addition to depressed delayed hyper sensitivity and profound lymphocytopenia, these individuals may patient appears to be unable to support the initial transfer display hypogammaglobulinemia and poor antibody formation. reaction of normal lymphocytes (R i ). Such terminal patients Added to the poor reaction of transferred Hodgkin's cells (D Â¿) have a complex immunologie defect to which therapy and and poor in vitro function, the skin of the terminal Hodgkin's debility undoubtedly contribute, and it is not unlikely that this

1156 CANCER RESEARCH VOL. 26

TABLE 8 IMMUNOLOGICUNRESPONSIVENESSANDDISEASESTATUSIN HODGKIN'SDISEASE

HYPERSENSITIVITYDelayedallergensNiIIMMUNITYAntibodyNN?N?1Y-globulinNNN1LYMPHOCYTECOUNTNor

STATUSLocalizedDISEASE TRANSFER REACTIOND|DiDl.RiLYMPHOCYTEIÂ»vitro(1)(1) sensi tization (DNCB)Â°Ni11HUMORAL

(inac tive orhealed)Localized (active)GeneralizedTerminalDELAYED 11 or 1I1 oru1 1Active 1LYMPHOCYTE 0 DNCB, dinitrochlorobeuzeiie; N = normal; | , depressed; i |, markedly depressed; D, reaction of transferred Hodgkin's lymphocytes (donor); R, reaction of normal lymphocytes in Hodgkin's re cipient. Parentheses indicate preliminary finding. See the text for details. terminal immunologie state shares common and nonspecific In recent years, immunologists have observed in experimental features with that of terminal carcinoma (43). animals 2 separate, usually fatal diseases of lymphoid tissue It should be emphasized that Table 8 is a tentative formula whose origin can be traced to specific manipulations. What is tion. The very division of a continuous spectrum of disease and the relationship of these immunologie entities to Hodgkin's immune alteration into 4 separate categories is, of itself, an disease? approximation. It must also be apparent that despite the previous The 1st of these diseases, the graft versus host reaction, is seen discussion, one understands very little of what is going on behind in a variety of situations where immunologically competent, the immunologie scenes in Hodgkin's disease. There are several genetically foreign, lymphoid cells are transferred to a host features which suggest a peripheral failure of the effector lymph- unable to reject the lymphoid graft (68). Among the frequently oid cell rather than a central one (tolerance) (48). Depression of observed features of the graft versus host reaction are lymph- delayed hypersensitivity in the face of essentially normal anti adenopathy, splenomegaly, leukocytosis, skin lesions, diarrhea, body formation and the recovery of skin allergy during disease anemia (which may be hemolytic), thrombocytopenia, wasting, remission (without further antigen exposure) imply an intact runting in the newborn, and death (14, 54, 59, 68). Kaplan and central mechanism. The abnormalities of Hodgkin's lymphocytes Smithers (37) have pointed out similarities between graft versus when cultured and after transfer studies support such a conten host reactions and the malignant lymphomas, and Green (32) tion. The failure of Kelley et al. (38) to transfer delayed hyper- has raised the question of whether the patient with Hodgkins sensitivity with peripheral lymphoid cells (42) from hypersensi disease could be a maternal-fetal lymphoid chimera. While the tive normals to anergic Hodgkin's patients does not settle this similarities to Hodgkin's disease of the above reaction are point, and unfortunately the more critical converse experiment obvious, at the present time the evidence that they play a role (the transfer from sensitized but anergic Hodgkin's patients to in the pathogenesis of Hodgkin's disease is not compelling. Graft normal individuals) has numerous practical and theoretical versus host reactions lack 2 important features of Hodgkin's difficulties. disease: the infection-like picture of the disseminated process In late Hodgkin's disease the severe depletion of blood and with chills and fever and the histologie picture characterized by tissue lymphocytes probably contributes to the complex immuno Reed-Sternberg cells. Finally, the available evidence suggests logie abnormalities observed. However, in the early case where that the immunologie defect in graft versus host reactions the disease process is quite localized and lymphoeytopenia the involves both antibody formation and delayed hypersensitivity exception, the defect in peripheral lymphoid cells must be (35). qualitative rather than quantitative. The 2nd experimental entity which bears some resemblance A point worth noting is the evidence that hypersensitivity to to Hodgkin's disease is the wasting condition observed in tuberculin is depressed during the acute stage of measles (58) thymectomized animals (27, 51, 56, 67, 76), which is char and other virus infections (53). Indeed, it has recently been acterized by lymphocytopenia, severe depletion of tissue lympho shown that the tuberculin reaction frequently becomes negative cytes (but not plasma cells), diarrhea, wasting, and death (51, during the incubation period of measles, is uniformly negative 56, 67). While the point has not been definitely proven, recent for the 1st 4 days of the rash, and is often depressed even after evidence, particularly the absence of wasting in thymectomized immunization with live virus vaccine (70). While these observa germ-free animals (47), points to an infectious etiology of this tions hardly offer a complete explanation for the anergy of syndrome. Decreased resistance to infection is to be anticipated Hodgkin's disease, they would be consistent with a virus causa since in several species, the neonatally thymectomized animal tion of the condition (2). However, it should be remarked that or the irradiated-thymectomized adult (7, 52) is immunologically unlike Hodgkin's disease, where anergy accompanies a localized impaired. In the best studied species, the mouse (27, 51), neonatal process, in measles the pathologic involvement of lymphoid thymectomy leads to a depression of antibody formation and tissue is severe and generalized (62). The anergy of sarcoid also homograft rejection, and similar findings are observed in the differs from that of Hodgkin's disease in that the granulomatous rat (76), where delayed hypersensitivity is also found to be process is generalized, and in several other details as well (28). depressed.

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The specific question with regard to Hodgkin's disease is what Interpretation of Mechanisms of Graft Rejection. Progr relationship, if any, there is between the thymectomy-wasting Allergy, 6: 468-538, 1962. syndrome and the human condition. The similarity of 2 wasting 9. Arenas, T., Coonrad, C. V., and Rundles, R. W. Serum Pro teins in Hodgkin's Disease and Malignant Lymphoma. Am. diseases of lymphoid origin with associated immunologie impair J. Med., 16: 833-41, 1954. ment is obvious. Lymphoid depletion and the susceptibility to 10. Aspinall, R. L., and Meyer, R. K. Effect of Steroidal and Sur secondary infection offer further analogies. However, the gical Bursectomy and Surgical Thymectomy on the Skin thvmectomy-wasting syndrome would not seem to account for the form of presentation of localized Hodgkin's disease, the Ilomograft Reaction in Chickens. In: R. A. Good and A. E. Gabrielsen (eds.), The Thymus in Immunobiology, pp. 376-94. histologie picture (Reed-Sternberg cells), or the chills, fever, and New York: Hoeber-Harper, 1964. leukocytosis of disseminated disease. Furthermore, in the 11. Bain, B., Vas, M. R., and Lowenstein, L. The Development of neonatally thymectomized animal, in contrast to the Hodgkin's Large Immature Mononuclear Cells in Mixed Leukocyte Cul patient, lymphocyte depletion tends to occur early and the tures. Blood, 23: 108-16, 1964. depression of antibody formation may parallel the depression of 12. Barr, M., and Fairley, G. H. Circulating Antibodies in Reticu- loses. Lancet, /: 1305-10, 1961. delayed hypersensitivity. Despite these several objections, the recent elucidation of 13. Beilby, J. O. W., Cade, I. S., Jelliffe, A. M., Parkin, D. M., and Stewart, J. W. Prolonged Survival of a Bone Marrow Graft thymus function does seem to bring nearer comprehension of the immunologie defect of the Hodgkin's patient. Perhaps neonatal Resulting in Blood-Group Chimera. Brit. Med. J., /: 96-99, thvmectomy and Hodgkin's disease lead to a similar end stage 1960. 14. Billingham, R. E., Defendi, V., Silvers, W. K., and Stein- of lymphoid and immunologie exhaustion, but via different muller, D. Quantitative Studies on the Induction of Toler mechanisms. [In this connection the parallel between the Swiss ance of Skin Homografts and on Runt Disease in Neonatal form of agammaglobulinemia (25, 29),a condition characterized by Rats. J. Nati. Cancer Inst., 28: 365-435, 1962. lymphocytopenia, thymic hypoplasia, frequent bacterial and 15. Billingham, R. E., and Silvers, W. K. Sensitivity to Homo- fungal infections, and early death, and the immunologie state of grafts of Normal Tissues and Cells. Ann. Rev. Microbiol., 17: the patient with advanced Hodgkin's disease should be men 531-64, 1963. 16. Brent, L., and Medawar, P. B. 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Alan C. Aisenberg

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