Insulin-dependent diabetes mellitus induced by subdiabetogenic doses of streptozotocin: obligatory role of cell-mediated autoimmune processes.

The role of thymic functions in the development of insulin-dependent diabetes was investigated in athymic nude (nu/nu) mice and euthymic heterozygous (+/nu) littermates of BALB/c origin treated with streptozotocin. The injection of a single high dose of streptozotocin (200 mg/kg body weight) induced rapid and permanent hyperglycemia in both nu/nu and +/nu mice. In contrast, the injection of the same total dose divided into multiple "subdiabetogenic" doses (40 mg/kg per day for 5 consecutive days) caused the development of delayed but progressive hyperglycemia only in the thymus-competent +/nu mice. Female mice of either genotype were significantly less susceptible to streptozotocin at both doses. Restoration of thymic immunity in nu/nu mice by thymus grafts also restored the susceptibility to the hyperglycemic effects of multiple low doses of streptozotocin. Moreover, splenic lymphocytes from +/nu mice previously made diabetic with the multiple low-dose injections of streptozotocin induced transient glucose intolerance in nu/nu mice. The ability of the diabetic spleen cells to transfer the diabetic state was abolished when the splenic lymphocytes were depleted of the T cells but not when they were depleted of B cells. These results provide direct proof that thymus-dependent functions play an obligatory etiologic role in the development of diabetes in mice treated with repeated subdiabetogenic doses of streptozotocin. These observations also add to the growing evidence that autoimmune amplification mechanisms may be critically involved in the etiology of juvenile-onset diabetes mellitus in humans.     

Cellular immunity to the mouse pneumonitis agent

During infection with the mouse pneumonitis biovar of Chlamydia trachomatis, heterozygous (nu/+) mice with relatively intact T cell function develop both delayed hypersensitivity to C trachomatis antigen and antigen-specific lymphocyte transformation, whereas athymic nude (nu/nu) mice do not. Nu/nu mice are protected against death from mouse pneumonitis by transfer of immune T cells from nu/+ mice, which are more resistant to C trachomatis. While this enables athymic mice to make antibody to C trachomatis (which does not occur without reconstitution), resistance correlates best with development of antigen-specific lymphocyte transformation in the recipient animals. During infection nu/+ mice develop activated alveolar macrophages (by both morphological and functional criteria) while nu/nu mice do not. Nu/+ mice that have been preinfected with Histoplasma capsulatum to activate cellular immunity become more resistant to C trachomatis than do nu/+ controls. Cell-mediated immunity to C trachomatis pneumonia is T cell dependent and is important in host defense.     

In vivo significance of T cells in the development of Coxsackievirus B3 myocarditis in mice. Immature but antigen-specific T cells aggravate cardiac injury.

Acute myocardial damage similar to that seen in human myocarditis occurs in BALB/c mice after infection with coxsackievirus B3 (CB3) or encephalomyocarditis virus (EMC). To investigate the role of antigen-specific T cells in the pathogenesis of this disorder, we compared CB3 disease expression in T cell-deficient, athymic nude (nu/nu) mice, in heterozygote (nu/+) mice with normal T cell function, and in nu/nu mice reconstituted with spleen cells from CB3- or EMC-infected nu/+ mice. Acute myocarditis occurred in both nu/nu and nu/+ mice. Severe myocarditis, however, developed only in nu/+ and nu/nu mice reconstituted with CB3-sensitized T cells, but not in those reconstituted with EMC-sensitized T cells. Myocardial virus titer and serum anti-CB3 antibody production were similar in nu/+ and nu/nu groups. Additionally, the presence of Thy 1.2 (pan T), Ly 1 (precursor of other T cell subsets), and Ly 2 (suppressor/cytotoxic T) positive cells was demonstrated in the myocardium in nu/+ and nu/nu mice reconstituted with CB3-sensitized T cells, but not with T cells sensitized by another virus, EMC. These results indicate that immature but antigen-specific T cells play a role in the pathogenesis of ongoing myocarditis.     

Comparison of leukocytes obtained from the intestinal lumen of Giardia-infected immunocompetent mice and nude mice

Previous studies have suggested that Giardia infections are cleared immunologically, but have not defined the mechanism of clearance. The aim of the present work was to compare subpopulations of leukocytes harvested from the intestinal lumen of immunocompetent BALB/c mice, which clear Giardia muris infection rapidly, with those of immunodeficient nude mice, which become chronically infected with Giardia muris. Leukocytes were obtained from the intestinal lumen of Giardia-infected mice, and subpopulations of these cells were quantified after immunofluorescent staining with monoclonal antibodies. Identical numbers of leukocytes were harvested from the intestinal lumen of Giardia-infected immunocompetent mice and nude mice, but the number of these leukocytes bearing the T-lymphocyte antigen Thy-1.2 was smaller in nude mice than in immunocompetent mice. In contrast, no striking differences were observed between the numbers of luminal cytotoxic/suppressor T lymphocytes or macrophages in Giardia-infected nude versus immunocompetent mice. The findings suggest that clearance of Giardia muris infection is not mediated by cytotoxic T lymphocytes or macrophages. Subsequently, T lymphocytes and T-lymphocyte subsets were quantified in cell suspensions prepared from Peyer's patches of immunocompetent BALB/c mice and nude mice. It was found that nude mice have a profound deficiency of Peyer's patch helper/inducer T lymphocytes. This deficiency may account for the inability of nude mice to clear Giardia muris infection at a normal rate.     

Enhancement of bone marrow allografts from nude mice into mismatched recipients by T cells void of graft-versus-host activity.

Transplantation of 8 x 10(6) C57BL/6-Nu+/Nu+ (nude) bone marrow cells into C3H/HeJ recipients after conditioning with 8 Gy of total body irradiation has resulted in a markedly higher rate of graft rejection or graft failure compared to that found in recipients of normal C57BL/6 or C57BL/6-Bg+/Bg+ (beige) T-cell-depleted bone marrow. Mixing experiments using different numbers of nude bone marrow cells with or without mature thymocytes (unagglutinated by peanut agglutinin) revealed that engraftment of allogeneic T-cell-depleted bone marrow is T-cell dependent. To ensure engraftment, a large inoculum of nude bone marrow must be supplemented with a trace number of donor T cells, whereas a small bone marrow dose from nude donors requires a much larger number of T cells for engraftment. Marked enhancement of donor type chimerism was also found when F1 thymocytes were added to nude bone marrow cells, indicating that the enhancement of bone marrow engraftment by T cells is not only mediated by alloreactivity against residual host cells but may rather be generated by growth factors, the release of which may require specific interactions between T cells and stem cells or between T cells and bone marrow stroma cells.     

Antibody-targeted superantigens are potent inducers of tumor-infiltrating T lymphocytes in vivo.

Recruitment of antigen-specific tumor-infiltrating lymphocytes (TILs) is a major goal for immunotherapy of malignant tumours. We now describe that T-cell-activating superantigens targeted to a tumor by monoclonal antibodies induced large numbers of pseudospecific TILs and eradication of micrometastases. As a model for tumor micrometastases, syngeneic B16 melanoma cells transfected with the human colon carcinoma antigen C215 were injected intravenously into C57BL/6 mice and therapy with an anti-C215 Fab fragment-staphylococcal enterotoxin A (C215Fab-SEA) fusion protein reacting with the C215 antigen was initiated when visible lung metastases were established. More than 90% reduction of the number of lung metastases was observed when mice carrying 5-day-old established lung metastases were treated with C215Fab-SEA. The antitumor effect of C215Fab-SEA was shown to be T-cell-dependent since no therapeutic effect was seen in T-cell-deficient nude mice. Depletion of T-cell subsets by injection of monoclonal antibody demonstrated that CD8+ cells were the most prominent effector cells although some contribution from CD4+ cells was also noted. C215Fab-SEA treatment induced massive tumor infiltration of CD4+ and CD8+ T cells, while only scattered T cells were observed in untreated tumors. SEA treatment alone induced a slight general inflammatory response in the lung parenchyme, but no specific accumulation of T cells was seen in the tumor. TILs induced by C215Fab-SEA were mainly CD8+ but a substantial number of CD4+ cells were also present. Immunohistochemical analysis showed strong production of the tumoricidal cytokines tumor necrosis factor alpha and interferon gamma in the tumor. Thus, the C215Fab-SEA fusion protein targets effector T lymphocytes to established tumors in vivo and provokes a strong local antitumor immune response.     

Requirements for flare reactions of joint inflammation induced in mice by cloned MT4+, Lyt-2- T cells

Joint inflammation was induced in C57B1/6 mice by injection of cloned MT4+, Lyt-2- T cells specific for the antigen methylated bovine serum albumin (mBSA), together with mBSA. In this model, after waning of the inflammation, flare reactions can be induced by a rechallenge with the specific antigen. Herein we show that such flare reactions can still be induced several weeks after waning of the joint inflammation, as was demonstrated both in normal C57B1/6 mice and in athymic C57B1 nude mice. The results in the latter group indicate that T cells of the recipient mice are not necessary for the elicitation of flare reactions. On histologic examination, the inflammatory infiltrates in the knee joints of the nude mice appeared to be mainly granulocytic. The cloned T cells persisted and remained functionally reactive in the knee joint for at least 2 weeks in the absence of the antigen, and thus, in the absence of inflammation. In view of the similarities between induced joint inflammation in mice and rheumatoid arthritis in humans, these data may be relevant to our understanding of the processes involved in the latter disease.     

Functional T cells in athymic nude mice.

After passage of spleen cells from nu/nu mice over a nylon wool column, concanavalin A-responsive cells can be detected in the presence of 2-mercaptoethanol, and specific cytotoxic T lymphocytes can be generated without exposure to interleukin 2 (IL-2). The spleen cells of the nu/nu mice born of nu/nu parents and nursed by nu/nu mothers had significantly fewer Thy-1+ T cells and a lesser capacity to generate cytotoxic T lymphocytes than did the conventionally bred nu/nu mice. Nonetheless, such cells were clearly present. IL-2 may act to cause these post-thymic T cells to proliferate. Therefore, it seems inappropriate to consider IL-2 as an inducer of the differentiation of T cells in the absence of thymic influence on the basis of the capacity of IL-2 to induce the appearance of a T-lymphocyte population in nu/nu mice.     

Genetic deficiency of alpha1-PI in mice influences lung responses to bleomycin.

It has recently been suggested that proteinase inhibitors modulate the fibrotic response in the lung. This study investigated the development of bleomycin-induced pulmonary changes in pallid mice, deficient in serum alpha1-proteinase inhibitor, and with a lower elastase inhibitory capacity, and in congenic C57Bl/6J mice. Male pallid and C57Bl/6J mice received a single intratracheal instillation of either saline or bleomycin. The investigation was carried out by means of biochemical, morphological and morphometrical methods. In both strains, 21 and 72 h after bleomycin, the lungs showed foci of inflammatory cell infiltration associated with emphysema. Fibrosis developed with time after bleomycin. At 14 days fibrosis affected 23.46+/-9.48% (mean +/- SD) and 40.62+/-13.34% (p < 0.01) of the lungs of C57Bl/6J and pallid mice, respectively. Emphysema affected 3.68+/-3.11% and 12.57+/-4.13% (p<0.01) of lung in C57Bl/6J and pallid mice, respectively. In C57Bl/6J mice bleomycin increased lung hydroxyproline content by 34% and desmosine content by 44% (p < 0.01 for both). In pallid mice these increases were only 21% (p < 0.01) and 6% which may reflect parenchymal loss. Thus, the lung destructive response (emphysema) and the subsequent proliferative reaction (fibrosis) to bleomycin are potentiated in alpha1-proteinase inhibitor deficiency.     

NEUROENDOCRINE ALTERATIONS IN NUDE MICE WITH A HUMAN LUNG CARCINOMA PRODUCING PRO-OPIOMELANOCORTIN, CORTICOTROPHIN-RELEASING HORMONE AND ARGININE VASOPRESSIN

A mucoepidermoid carcinoma of the lung (ICD classification 8430/3) resected from a patient with no clinical signs of pituitary-adrenal alterations was transplanted into 2-month-old athymic nu/nu nude mice, with the purpose of studying the effects exerted by the human tumour on the host hypothalamo-pituitary-adrenal axis. The tumour produces peptides derived from different regions of pro-opiomelanocortin (POMC: ACTH, 7.6 +/- 0.7; N-terminal POMC, 6.6 +/- 0.6; beta-LPH/endorphin, 7.3 +/- 0.7; and alpha-MSH;3.8 +/- 0.5 pmol/g wet tissue) and the neuropeptides corticotrophin-releasing hormone and arginine vasopressin (CRH: 3.6 +/- 0.4 and AVP: 1.1 +/- 0.2 pmol/g wet tissue). Immunohistochemical staining of consecutive sections of the tumour indicated that staining of tumour cells for the different peptides was not uniform and although some cells co-stained with CRH and AVP, POMC-positive cells appeared to be distinct from CRH and AVP cells. Tumour extracts were chromatographed on Sephadex G-75 and fractions monitored for POMC-derived peptides. A single peak with characteristics of alpha-MSH was detected. The ACTH, N-POMC and beta-LPH/endorphin radioimmunoassays (RIA) detected a peak at large molecular weight, eluting at the position expected for POMC. These RIA systems also revealed an ACTH(1-39) peak and another peak which probably correspond to 13 kDa ACTH, a peak eluting at the position of hN-POMC(1-48), a beta-LPH-like peak, and a smaller sized peak which may represent alpha- or gamma-endorphin. The ACTH, N-POMC and beta-LPH/endorphin contents of anterior lobe (AL) extracts, but not neutrointermediate lobe (NIL) extracts, showed a striking decrease in tumour-bearing (TB) nude mice. However, while no difference was seen in the alpha-MSH content of AL extract between TB and control (C) nude mice, it decreased in NIL extracts of TB animals. The contents of CRH and AVP in stalk-median eminence extracts of TB nude mice was significantly lower than that of C nude mice. Basal plasma corticosteroids were raised in TB nude mice at levels comparable to those in stressed C nude mice, and although adrenal weights did not vary between TB and C nude mice, morphological changes indicating hypertrophy were found in the adrenal glands of the host animals. It was concluded that the tumour dramatically alters the hypothalamo-pituitary-adrenal axis of the host, and that it may be a useful model for studying tumour-host interactions in ectopic hormone-producing tumours.     

Control of hemopoiesis in mice by sensitized L3T4+ Lyt2-lymphocytes during infection with bacillus Calmette-Guérin.

When injected intravenously with bacillus Calmette-Guérin (BCG; 10(7) viable units), C57BL/6 mice rapidly develop a transient anemia associated with an increased number of granulocytes and monocytes, whereas C3H/He mice do not. Because these two features are lacking in C57BL/6 nude mice we postulated that T lymphocytes can regulate hemopoiesis during infection. To assess further the role in hemopoiesis of T lymphocytes present in bone marrow of C57BL/6 and C3H/He mice, the frequency of BCG-specific T lymphocytes and their surface marker phenotype were determined by limiting dilution analysis and use of monoclonal antibodies. The number of BCG-specific T lymphocytes was estimated to be 50- to 100-fold higher in bone marrow of C57BL/6 than in that of C3H/He mice. Although L3T4+ Lyt2-and L3T4- Lyt2+ BCG-specific T lymphocytes were generated in mice of both strains, in C57BL/6 mice L3T4+ cells were induced preferentially from day 1 through day 5 after infection in correlation with hemopoietic changes. The relation between T-cell immune response and hemopoietic changes was substantiated by results obtained after in vivo treatment with monoclonal antibodies. Selective depletion of L3T4+ T cells by in vivo injection of anti-L3T4 monoclonal antibodies (GK 1-5) inhibited the development of the anemia and the related increased production of phagocytes in C57BL/6 mice receiving BCG.     

Kinetics of Small Lymphocytes in Normal and Nude Mice after Splenectomy

Autoradiography and various quantitations on lymphoid tissues have been used to evaluate the kinetics of small lymphocytes in normal (+/nu or +/+) and congenitally athymic nude (nu/nu) NMRI mice 1 month after splenectomy or sham-splenectomy. The results indicate that splenectomy causes depressed thymic activity and diminished numbers of T lymphocytes in peripheral lymphoid tissues. The total number of cells in these tissues as well as the blast cell activity, were within normal limits. Bone marrow lymphocyte numbers and kinetics as well as blood lymphocyte levels in splenectomized and sham-splenectomized normal animals were comparable. Blood lymphocyte numbers were at normal levels in splenectomized nude mice, in spite of reduced numbers of bone marrow and thoracic duct lymphocytes. It is suggested that increased number of newly-formed lymphocytes, found in lymph nodes and blood of splenectomized mice, are released from the lympho-myeloid organs in compensation for the loss of long-lived, thymus-derived cells.     

Rapid thymomas induced by Abelson murine leukemia virus.

Abelson murine leukemia virus (A-MuLV) is derived from the thymotropic Moloney leukemia virus. However, injection of mice with A-MuLV by conventional routes results in rapidly arising peripheral and bone marrow lymphomas, not thymomas or T cell tumors. In this study thymomas have been induced by intrathymic injection of A-MuLV into BALB/c and C57BL/Ka mice. In both strains thymomas arose with short latent periods, comparable with the latencies of nonthymic tumors induced by intraperitoneal injection of A-MuLV and significantly shorter than those of thymomas induced by intrathymic injection of Moloney leukemia virus. Cells of the BALB/c thymomas were predominantly Thy-1-; those of C57BL/Ka thymomas were predominantly Thy-1+. Tissue culture lines were established and cloned. Some of these expressed low amounts of Thy-1 and one also expressed Lyt-1. Virus from cloned lines transformed 3T3 cells in vitro and induced Abelson disease in vivo when injected intraperitoneally into neonates. The A-MuLV p120 protein has been precipitated from metabolically labeled cell lysates of one cloned Thy-1+ line. These results show that A-MuLV can transform cells in the T lymphocyte lineage.     

Induction of intestinal lesions in nu/nu mice induced by transfer of lymphocytes from syngeneic mice infected with murine retrovirus

T Mizuochi,^dH Asakura,^bM Fujiwara^a

Background—Murine leukemia virus, LP-BM5, inducessevere immunodeficiency with abnormal lymphoproliferation insusceptible C57BL/6 mice. In a previous study, it was shown that aSjögren's syndrome-like systemic exocrinopathy is induced in thevirus infected mice.
Aims—To examine lymphocyte functions of the virusinfected mice.
Methods—Four-week old mice were inoculated withthe virus and their spleen cells were transferred into syngeneic nu/numice. Their organs were examined by light and electron microscopy.Phenotypes of the colon infiltrating cells were examined by flow cytometry.
Results—All nu/nu recipients had died by six weeksafter cell transfer, showing runting disease like cachexia withdiarrhoea and anal bleeding. Histopathological examination revealedthat systemic exocrinopathy was adoptively transferable and that the colon became thickened due to mononuclear cell infiltration into themucosal and submucosal layer with hyperplasia of intestinal epithelialcells. No virus particles were found in the colon. Flow cytometricanalyses revealed that most of the infiltrating CD4+ T cells showedCD45RB^low. No intestinal lesions were observed in the virusinfected mice nor in nu/nu mice inoculated with normal lymphocytes.
Conclusion—Lymphocytes of the virus infected miceinduced colitis and hyperplasia of intestinal epithelial cells as wellas systemic exocrinopathy in nu/nu mice. Our experimental system maygive some insight into intestinal lesions associated with virus infection.

Keywords:murine leukemia virus; nude mice; enterocolitis; colitogenic cells

     

Progressive growth in immunodeficient mice and host cell recruitment by mouse endothelial cells transformed by polyoma middle-sized T antigen: implications for the pathogenesis of opportunistic vascular tumors.

A retroviral construct encoding polyoma middle-sized T antigen was used to generate transformed endothelial cell lines from heart (H5V), brain (B9V), and whole-embryo (E10V) of C57BL/6 mice. When injected into syngeneic recipients, H5V and the less studied B9V and E10V cells caused vascular tumors which, depending on the number of cells inoculated, regressed or progressed, leading to death of the host. When H5V cells were injected into immunodeficient mice, tumors were observed with inocula which did not form lesions in immunocompetent recipients and regression did not occur. Treatment with anti-LFA-1, anti-Thy-1.2, and anti-CD8 antibodies abolished rejection; anti-CD4 was a somewhat less effective inhibitor of resistance. Animals with progressive tumors exhibited secondary lesions in various organs with prominent skin involvement in nude mice. Histologically, the tumors had the appearance of a hemangioma, with areas resembling Kaposi sarcoma. Cells lining vascular lacunae had the morphological features of injected H5V cells. The lesions were characterized by prominent neovascularization and mononuclear cell infiltration. Southern blot hybridization analysis revealed that approximately 5% of the cells in the tumor mass were transplanted H5V cells. Thus, the H5V transformed endothelial line causes vascular lesions that are sustained to a large extent by recruitment of host cells and manifests full malignant behavior only in immunocompromised hosts. The hypothesis of a tumor sustained by a minute proportion of transformed cells, which recruit host elements and express full malignant behavior only in immunodeficient hosts, would account for several features of some vascular neoplasms in man.     

Influence of FHIT on benzo[a]pyrene-induced tumors and alopecia in mice: chemoprevention by budesonide and N-acetylcysteine

The FHIT gene has many hallmarks of a tumor-suppressor gene and is involved in a large variety of cancers. We treated A/J mice and (C57BL/6J x 129/SvJ)F1 (B6/129 F1) mice, either wild-type or FHIT+/-, with multiple doses of benzo[a]pyrene (B[a]P) by gavage. B[a]P caused a time-related increase of micronuclei in peripheral blood erythrocytes. Both A/J and B6/129 F1 mice, irrespective of their FHIT status, were sensitive to induction of forestomach tumors, whereas B[a]P induced glandular stomach hyperplasia and a high multiplicity of lung tumors in A/J mice only. Preneoplastic lesions of the uterus were more frequent in FHIT+/- mice. B6/129 F1 mice underwent spontaneous alopecia areata and hair bulb cell apoptosis, which were greatly accelerated either by FHIT heterozygosity or by B[a]P treatment, thus suggesting that FHIT plays a role in the pathogenesis of alopecia areata. The oral administration of either budesonide or N-acetyl-L-cysteine (NAC) inhibited the occurrence of this inflammatory skin disease. In addition, these agents prevented B[a]P-induced glandular stomach hyperplasia and decreased the size of both forestomach tumors and lung tumors in A/J mice. Budesonide also attenuated lung tumor multiplicity. In B6/129 F1 mice, NAC significantly decreased the proliferating cell nuclear antigen in lung tumors. Both budesonide and NAC inhibited B[a]P-induced forestomach tumors and preneoplastic lesions of the respiratory tract in B6/129 F1 mice. In conclusion, heterozygosity for FHIT affects susceptibility of mice to spontaneous alopecia areata and B[a]P-induced preneoplastic lesions of the uterus and does not alter responsiveness to budesonide and NAC.     

Long-standing hyperglycemia in C57BL/6J mice does not affect retinal glutathione levels or endothelial/pericyte ratio in retinal capillaries

Free radicals have been suggested to play a role in the development of diabetic retinopathy. The aim of the present study was to examine whether the metabolic perturbations caused by high-fat feeding of two strains of mice, the C57BL6/J mice and the NMRI mice, interfere with one of the free radical enzyme defense systems in the retina, i. e., glutathione (GSH), and whether morphological changes occur in the retinal vessels. C57BL/6J mice and NMRI mice were fed a high-fat diet (55%) for 18 months. High-fat fed mice of both strains developed overweight, hyperinsulinemia, and hyperlipidemia. In addition, the high-fat fed C57BL/6J mice also developed sustained hyperglycemia for at least 15 months. The C57BL/6J mice had lower retinal GSH levels than the NMRI mice, both when given a normal diet (29.6+/-1.2 vs. 37.1+/-1.4 nmol/mg protein; p<0.01) and when given a high-fat diet (27.0+/-1.6 vs. 34.7+/-2.6 nmol/mg protein; p<0.05). Despite the long-standing hyperglycemia, hyperinsulinemia and hyperlipidemia in the C57BL/6J mice, high-fat feeding did not cause any changes in the retinal tissue levels of GSH (27.0+/-1.6 vs. 29. 6+/-1.2 nmol/mg protein) or cysteine (7.61+/-0.63 vs. 6.80+/-0.59 nmol/mg protein). Similarly, high-fat feeding did not affect retinal GSH or cysteine levels in NMRI mice. No light microscopical retinal vessel changes were seen, either in C57BL/6J or in NMRI mice. The study therefore shows that long-standing metabolic perturbations induced by dietary obesity do not induce signs of retinopathy in two different strains of mice. Further studies are needed to explore whether this is explained by increased expression of protecting systems making these strains of mice resistant to effects of oxidative stress.     

Host defense in cryptococcosis. III. Protection of nude mice by thymus transplantation.

Congenitally athymic (nude) BALB/c mice, which are homozygous for the nu gene, are extremely susceptible to challenge with Cryptococcus neoformans. Groups of nude mice received transplants of thymus tissue obtained from either heterozygous (nu/+) mice or normal BALB/c mice not carrying the nu gene. Survival and delayed-type hypersensitivity were measured after challenge with cryptococci. Mice that received thymus tissue from a heterozygous (nu/+) or normal BALB/c mouse donor had markedly prolonged survival after challenge. In addition, mice that received thymus tissue from normal BALB/c mice developed delayed-type hypersensitivity to cryptococcal antigens following challenge. These studies indicate that transplantation of thymus tissue effectively increases host immune resistance against C. neoformans.     

Effect of graft-versus-host reaction on the immune response to alloantigens and growth of a syngeneic tumor.

The graft-versus-host reaction (GVHR) was evoked in (C57BL/6J times C3H/6J times DBA/2J) F1 hybrids by grafting parental lymphoid cells. Groups of bothe F1 hybrids were immunized with thymocytes carrying Thy-1.1 (theta AKR) antigen and still other groups of (C57BL/6J times C3H/HeJ) F1 hybrids were immunized with thymocytes carrying the H-2-d antigen. Plaque-forming cells (PFC) producing antibodies to the Thy-1.1 antigen, lytic for AKR thymocytes, or antibodies to the H-2-d antigen, lytic for lymphoblasts carrying the H-2-d antigens, were enumerated in spleens of experimental animals. A pronounced suppression of the immune response to the Thy-1.1 antigen was found in animals suffering from GVHR. The suppression could be demonstrated in some animals as late as 180 days after the onset of GVHR. Significant, although less pronounced suppression was found when response to the H-2-d antigens was assayed. After grafting 10-3 or 10-4 DBA/2J derived lymphoma cells (L5178Y) into (C57BL/6J times DBA/2J) F1 hybrids, clinically detectable tumor growth was found earlier and more frequently in hybrids suffering from GVHR than in control animals. The results obtained lend support to the concept that immunosuppression accompanying GVHR may influence the formation and/or growth of the malignant tumors. In addition, a synergistic effect in the suppression of the responsiveness of F1 recipients was seen in some instances when a mixture of parental bone marrow and thymus cells was grafted. The results are consistent with data indicating that more than one cell type is involved in the initiation of GVHR.