The recent observation that certain families of heat shock proteins (hsp) are strongly immunogenic and may be induced on cells exposed to various stressors has generated considerable interest in the field of autoimmunity. Thus it has been suggested that the expression of hsp may either elicit or exacerbate an immune-mediated attack against self tissue and, in particular, may activate a subset of T cells bearing the gamma- delta T cell receptor (gamma delta TcR). Consistent with this suggestion are recent observations from this laboratory showing in chronic-active lesions from patients with multiple sclerosis (MS) hsp 60 expression by oligodendrocyte at the lesion edge and the concomitant accumulation of gamma delta T cells. The significance of these findings remains to be defined. The objective of this proposal is to use an animal model of MS, experimental allergic encephalomyelitis (EAE), to investigate the potential contribution of hsp and gamma delta T cells to the primary demyelinating diseases. The hypothesis to be tested is that altered expression of hsp by cells endogenous to the central nervous system (CNS) serves as an additional target of the immune response, contributing to the pathologic expansion of the lesion and, in particular, to the development of chronic disease. We further hypothesize that the hsp response in glial is not a generic response to tissue injury, but shows a high degree of specificity in both the nature of the hsp expressed and the nature of the responding cell. These hypotheses will be tested principally in the chronic-relapsing model of EAE in the mouse induced by the passive transfer of sensitized T cells. In the first specific aim, qualitative and quantitative changes in the expression of hsp in the CNS will be assessed by immunocytochemistry, protein determination and analysis of mRNA levels at varying stages of the disease process. The second specific aim will analyze the immune response to hsp. The distribution of TcR alphaBeta and gamma delta T cells will be defined at various stages in the disease process and TcR gamma delta VDJ gene rearrangements and junctional sequences determined. The contribution of gamma delta T cells to disease expression will be examined by ablation and augmentation of these cells. Lymphoproliferative assays and ELISA will be used to quantitate lymphocyte responses. The final specific aim investigate factors that may regulate hsp expression by glial cells in vitro. The possible functional relevance of this expression will be examined by lymphocyte adhesion and cytotoxicity assays. These studies should, therefore, provide a comprehensive analysis of the potential relevance of hsp expression and gamma delta T cells to the pathogenesis of the demyelinating diseases.
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