MHC MODULATION WITHIN THE BRAIN

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Clinical interest in many areas (AIDS and other neural viral infections, multiple sclerosis (MS) and other demyelinating diseases, neural tumors, neural transplants) has focused attention on the immune response to neural antigens, and how it may be manipulated. The role of the major histocompatibility complex (MHC) in neural tissue is of interest in this context. MHC products mediate the interaction between T lymphocytes and antigen- bearing cells. Their absence protects infected, transformed, damaged and also transplanted neural tissue from T cell-mediated surveillance. Although MHC products are lacking from neurons and glia in normal brain, their expression is under regulatory control. We have begun to define the developmental and pathological situations in which greater MHC expression is seen, and regulatory mechanisms by which it can be manipulated. Here, we will continue this work, emphasizing the relevance to MS and other demyelinating diseases. Autoimmune damage mediated or initiated by T lymphocytes is important in the pathology of MS, and MHC modulation is seen in MS plaques. One therapeutic approach is to attempt to suppress the autoimmune response. One difficulty is that the target antigen(s) are not known, and they may not be the same in each patient. A general immunosuppression would also limit desirable immune reactions outside the nervous system. Learning more about the underlying biology of MHC modulation in the brain can contribute in two ways: It can help to define the significance of the MHC modulation seen in MS in terms of the etiology of the disease. Our work may also suggest ways in which MHC induction may be prevented selectively within the brain. (1) We will define the baseline MHC expression in normal brain, and the biosynthetic potential of neural cells to synthesize MHC products. (2) We will test the hypothesis that MHC expression is locally controlled in brain, and is normally actively suppressed. (3) We will test the hypothesis that glial cells regulate their own MHC expression, and perhaps that of neurons and endothelial cells as well. Immunocytochemical analysis of mouse tissue in situ, and immunocytochemical and biochemical analysis of murine and human cell lines will be used.