The induction of donor-specific tolerance in experimental renal allo-transplantation

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Although current immunosuppressive therapy for clinical organ transplantation has improved allograft survival, treatment-related complications of chronic drug administration still remain a major limitation to long-term success. Therefore, the major goal of clinical organ transplantation is to induce donor-specific transplantation tolerance. However, the mechanism of transplantation tolerance is still incompletely understood. (1) We examined to clarify the intra-renal allograft events associated with the development of tolerance in the tolerance induction protocol, and we indicated that both T cell anergy and T cell deletion occurred in the renal allografts during the development of tolerance. (2) We examined the characterization of renal allografts associated with the failure of tolerance induction in this protocol, and we also indicated that, in tolerance induction protocols, unstable tolerance induction was associated with the persistent immunological activation that mediated immunol … More ogical destruction of graft parenchymal cells in acute and/or chronic rejection. (3) We examined the process of the development of chronic rejection, because the leading cause of late kidney allograft failure is chronic rejection, yet little is known about its pathogenesis. Pathologically, chronic rejection was characterized by progressive interstitial fibrosis, tubular atrophy, chronic allograft glomerulopathy, and chronic allograft arteriopathy. The persistent rejection directed at PTCs and tubules, and proliferation of myofibroblasts were prominent features in the progressive interstitial fibrosis in chronic rejection, and were probably key events in its pathogenesis. The acute and persistent cell- and antibody-mediated rejection against glomerular and arterial endothelial cells was key pathogenic determinant of acute allograft glomerulopathy and acute endarteritis as well as progression to chronic allograft glomerulopathy and chronic allograft arteriopathy.We conclude that several strategies of active tolerance induction, which can induce specific immunologic unresponsiveness to the transplanted organ without prolonged administration of immunosuppressive agents is important in the organ transplantation. In treatment with tolerant induction protocol, rapid and stable tolerance induction is necessary for long term stable graft acceptance. Less