Trypanosoma cruzi infects up to 18 million individuals and is the major cause of heart disease in most of Latin America. Although the mechanism of pathogenesis in the chronic Chagas' disease is not understood, most available evidence supports a role for the immune system in the disease process. The experiments outlined in this proposal will directly address the participation of specific immune components including cytokines, cells and cell-related adhesion and activation molecules in Chagas' disease in a number of experimental mouse models. Our previous research has characterized the immune response directly.in the inflammatory site in experimental Chagas' disease, identifying the cells, adhesion molecules, and MHC Class I and Class II molecules within cardiac inflammatory lesions of T.cruzi-infected mice. We will continue this analysis, using immunohistochemistry and quantitative PCR for cytokine mRNAs and parasite rRNAs to obtain a comprehensive view of the immunological events occurring in the inflammatory sites in the chronic mouse model. In addition, we will develop, characterize and exploit a number of other systems as models for chronic Chagas' disease: a heart-transplant model which has been previously used in experimental Chagas' disease, a mouse/SAID mouse model for passive transfer of myocarditis, and transgenic mouse models in which the response to """"""""self"""""""" proteins can be easily studies and dissected. Using these models, we will determine if transplant rejection can be used to assess the presence and severity of Chagas' disease, if Chagas' disease can be transferred to naive animals, and if anti-self responses are important in the disease process. These models will provide significant new insights into the causes of Chagas' disease and will establish one or more systems in which disease develops rapidly and in which the immune response can be easily and quickly manipulated to directly determine the mechanism of the disease.process. A variety of therapies will be used to alter or block cytokine levels, adhesion or activation molecule interactions and cell infiltration into the heart. These therapies will be tested for their ability to prevent """"""""disease"""""""" in one or more of the experimental models scrutinized in AIM 2 and if successful, also tested in the chronically infected mouse model. While the primary purpose of these experiments will be to define the contribution of various immunological factors to disease, the results of these studies will also suggest methods for immunological intervention in Chagas' disease.
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