The protozoan parasite Trypanosoma cruzi is the causative agent of Chagas' disease, a sometimes debilitating disease characterized by digestive and cardiac dysfunction and failures. A major component of both the human and murine infection with this parasite is the induction of a long-lived immunosuppressed state. The long-term goals of this project are to understand both the mechanisms of the role for immunosuppression in determining the fate of the parasite in the infected host and the fate of the host in terms of development of pathology. Specifically the mechanisms regulating the anti-parasite and parasite-non-specific immune responses will be elucidated, with emphasis on the regulation of the humoral immune responses, and on the production of soluble lymphokine products by T cells from infected mice. The extent of suppression of lymphokine production will be determined, the biochemical and molecular basis for suppression of T cell activity defined, and the role of expression of T cell activation antigens in the failure of T cells from infected mice to produce lymphokines will be determined. The eventual goal of these experiments is to understand immunosuppression in this model sufficiently well to formulate treatment methods which will overcome immunosuppression. In addition, the response of T and B cells from infected or immunized mice to parasite antigens will be characterized and the antigens recognized by T cells identified using T cell western blots. Lastly, the question of the role of immunosuppression in allowing parasite survival and/or limiting the extent of pathology will be addressed. Lymphokines, immunoenhancing treatments, anti-lymphocyte antibody treatments and chemotherapy will be used as therapeutics to alter the course of infection and/or the intensity of anti-parasite immune response and to determine observe the effect of such treatments on the course of the disease. Mice treated in this fashion will be followed and the development of cardiac pathology determined. It is hoped that this study will establish the importance of immunoregulatory mechanisms as primary factors in determining the presence and extent of pathology in the murine infection, to identify the antigens important in stimulation of the T cells response and provide insight into possible treatment regimens for the human infection and disease.
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