NONRESPONSIVENESS TO CARDIAC ALLOGRAFTS INDUCED BY INTRATHYMIC INJECTION OF CLASS I ALLOPEPTIDES IS ASSOCIATED WITH LOCAL AND SYSTEMIC EXPRESSION OF TH2 CYTOKINES

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487 Intrathymic inoculation of donor antigens results in the induction of tolerance to allografts. We have recently demonstrated that cardiac allograft rejection in the PVG.R8-to-PVG.1U rat strains combination that is disparate for an isolated class I (RT1.Aa) MHC molecule, involves the recognition of this antigen as peptides presented by the recipient MHC molecules. Three synthetic peptides corresponding to variable portions ofα-helices of the α-1 and α-2 domains of the RT1.Aa molecule serve as CD4+ T cell epitopes for graft rejection. Intrathymic inoculation of the recipient with a mixture of these peptides results in immune nonresponsiveness to allografts in the majority of graft recipients (>75%). To study the underlying mechanisms of immune nonresponsiveness in this model, we studied intragraft as well as systemic expression of cytokines and intragraft deposition of alloantibodies in long-term grafts (>185 days), grafts with delayed (35-82 days) and normal rate of rejection (6-7 days). All the rejecting grafts had deposition of IgM, IgG1, IgG2a, IgG2b, and IgG2c. In contrast, long-term grafts had moderate deposition of only Th2 associated IgG1 and IgG2a and totally lacked other antibody subclasses. Rejected grafts had high levels of intragraft TNF-α and IFN-γ and moderate levels of IL-4. In marked contrast, long-term grafts had high levels of IL-4 and moderate to undetectable levels of IFN-γ and TNF-α. We also detected high levels (<10 nM) of IL-10 in the sera of long-term graft recipients. There was a gradual increase in the serum level of IL-10 starting 7-12 days after transplantation, which reached a plateau after 120 days and then declined to background levels after 200 days post-transplantation in the majority of graft recipients. Animals with acute rejection did not have detectable levels of IL-10. Regardless of the status of the graft, no systemic expression of IL-2, IL-4, and IFN-γ was found in any of the graft recipients. Taken together, our data provide clear evidence for the predominance of the Th2 pathway in long-term graft recipients. This pathway may plan an active role in maintaining graft survival by blocking the effector mechanisms of graft destruction induced by the Th1 pathway. This study was supported in part by grants from National Institutes of Health (AI 33587) and American Heart Association (9650229N).