In the process of investigating the nature of the immune response to alloantigens in rat models of organ transplantation, the applicants have employed synthetic peptides, which represent the polymorphic, antigenic motifs which can immunize or tolerize to MHC molecules. T lymphocyte recognition of such peptides is via the physiological pathway of antigen presentation by antigen presenting cells of the host, termed the indirect pathway of allo-recognition, because other clones of T cells recognize intact allo-MHC molecules directly on donor cells. The oral route of administration of donor antigen in the form of lymphocytes or synthetic peptides can suppress the development of the TH1 immune response in an antigen-specific manner, while intra-thymic injection produces a completely tolerant state, preventing acute and chronic rejection by tolerizing via the indirect pathway to donor class II MHC. The applicants hypothesized a failure to suppress T cell responses via the indirect pathway lies at the heart of the chronic rejection process. They plan to study human transplant recipients, based on preliminary results which show that patients having chronic renal allograft rejection have primed T cells to donor HLA-DR peptides. First, they will follow prospectively a series of transplant recipients over a three year period to determine their pattern of response to MHC allopeptides in relation to clinical events. The hypothesis is that responders will develop chronic rejection, while hyporesponsive patients are protected from developing the process. Second, they will generate allopeptide-specific T cell clones from examples of responsive and hyporesponsive patients, to define the HLA-restriction patterns as well as T cell receptor gene expression and cytokine patterns. Third, they will institute experiments of feeding the relevant donor HLA-DR peptides to patients with chronic rejection in an attempt to specifically down-regulate the immune response via the indirect pathway, as this will be an initial feasibility study towards development of new therapeutic strategies to prevent development or interrupt progression of chronic rejection.
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