Acute infection of mice with Trypanosoma cruzi results in severe immunodepression and the appearance of autoimmune symptoms. In vitro, concanavalin A-stimulated T cells from spleens of infected animals could neither produce nor respond to interleukin 2. Interleukin 2 production was not restored by addition of exogenous interleukin 1, and proliferative response to concanavalin A was not restored by exogenous interleukin 2. A population of Thy-i-negative cells in the spleen of infected animals was shown to suppress the concanavalin A proliferative response and, to a lesser extent, the production of interteukin 2. These and other symptoms of T. cruzi-infected mice are similar to the immune dysfunction of autoimmune Ipr/lpr mice. These findings are discussed in relationship to the pathology of Chagas disease.Trypanosoma cruzi causes Chagas disease in man. The disease is characterized by a variable acute phase during which trypomastigotes circulate, followed by a lifelong chronic phase in which parasites are not detected in circulation but rather appear to be sequestered in the tissues (1). The parasites persist in the chronically infected individuals in spite of the presence of high levels of circulating anti-T. cruzi antibodies. The mouse has been used as a laboratory model for Chagas disease because injection of parasites gives rise to both acute and chronic infections.Severe perturbations of the host immune system accompany T. cruzi infections in the mouse (1-4). On one hand, autoantibodies directed to various host antigens are induced. On the other hand, severe immunodepression has been reported to occur during the acute phase of the infection, and cellular responses to mitogens, parasite antigens, or irrelevant antigens are depressed. These results suggest that the parasites perturb the host immune system at the level of the T cells. We have studied this possibility by examining T-cell proliferation and the production of T-cell regulatory molecules in T. cruzi-infected mice.Interleukin 2 (IL-2) appears to play a key role in the regulation of cellular immune responses (5, 6). It is produced by T lymphocytes in the presence of interleukin 1 (IL-1) and mitogen or antigen, and it sustains the proliferation of helper and effector T lymphocytes and thus amplifies the effector phase of the immune response. Because of this central role of IL-2 in regulating the immune response, we have examined its production and activity in T. cruzi-infected mice.We report here that acute infection with T. cruzi results in a severe depression of IL-2 production which parallels the depressed proliferative response to the mitogen concanavalin A (Con A). Furthermore, Thy-l-spleen cells from infected animals are able to suppress the proliferative response to Con A and, to a lesser extent, IL-2 production by spleen cells from normal animals. MATERIALS AND METHODSMice and Infection. All experiments were performed with pools of three to eight C3H/HeJ Pas male mice (Pasteur Institute, Paris). Mice were 6-8 weeks of age at the time of...
Mice were acutely and chronically infected with Trypanosoma cruzi and then examined histologically for the presence of lesions in the peripheral nervous system. In acutely infected animals, small lymphocytic and macrophagic infiltrates were found in the nerves in association with intracellular parasites. Little or no nerve damage was present at this stage. In chronically infected animals, large perivascular granulomatous infiltrates were found in association with multifocal, predominantly demyelinative lesions of neighboring nerve fibers. Similar inflammatory infiltrates were present in muscles and were frequently associated with vasculitis and destruction of muscle fibers. Our pathological findings and the negative results produced by intraneural injections of sera from chronically infected animals and the positive results following injections of small numbers of live trypanosomes suggest that the demyelination is not due to circulating serum factors such as antibodies cross-reacting with peripheral myelin. Delayed-type hypersensitivity may be induced by the presence of the parasites, a notion supported by the development of granulomas in naive mice injected intravenously with helper T cells from chronically infected animals.
Normal C3H/HeJ mice, acutely infected with T. cruzi, develop large numbers of splenic Ig-secreting plaque-forming cells (PFC). IgG2a, IgG2b and IgG1 PFC account for over 90% of all PFC, while the numbers of IgG3- and IgA-secreting PFC are lower than in normal animals. These effects appear to be due to both T helper-dependent regulation and to a mitogenic activity associated with the parasites themselves.
Infection of mice with Trypanosoma cruzi results in a severe immunosuppression, accompanied by the appearance of autoimmune symptoms. We have previously shown that proliferation and interleukin 2 production by concanavalin A-stimulated T cells from infected mice is severely depressed. In this study we show that at least two phenomena are responsible for this depression. First, mixing experiments showed the existence, in spleens of infected animals, of adherent, Thy-1-negative and radioresistant suppressor cells. Second, studies of enriched T cell populations and analysis of precursors by limiting dilution showed that the T cell compartment itself was impaired in infected animals: responses of enriched T cells, even when reconstituted with normal accessory cells, reached only 40% of those obtained with normal uninfected mice.
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