TOLERANCE INDUCTION USING DST AND CYCLOSPORINE

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Blood transfusions are known to exert a powerful and long-lasting immunosuppressive effect which is both donor specific and non-specific. In laboratory animals, using the very stringent ACI to Lewis model of heterotopic cardiac allografts, the immunosuppressive effect of a single blood transfusion has been found to be maximal if it is given only 24 hours before the time of transplantation when cyclosporine is begun at the same time. When cyclosporine is continued at a low dose for only 30 days, and all immunosuppression discontinued, donor specific tolerance, with perm- anent survival of the graft occurs in some but not all animals. Recent studies have shown that a more efficient production of permanent tolerance can be achieved by a partial lymphocyte reduction using a monoclonal antibody immediately before the donor specific transfusion and by giving three additional transfusions during the first month post transplant. These findings provide a solid laboratory basis for using donor specific transfusions in recipients of cadaveric kidneys. Indeed, an initial ongoing randomized prospective study has shown that the use of cadaveric donor specific transfusions 24 hours before transplant, along with intravenous cyclosporine without an anti-lymphocyte globulin, has resulted in no occurrence of rejection episodes within the first six months post transplant and no loss of kidneys from rejection (9 patients treated so far). The current proposal is designed to test the additional modalities of a single dose of an anti T cell lymphocyte monoclonal antibody immediately before donor specific transfusion and cyclosporine induction in recipients of cadaveric kidneys who will also receive donor specific blood transfusions or bone marrow transfusions during the post transplant period. Since graft tolerance associated with administration of blood is an active immunologic process involving the development of specific macrophage and T lymphocyte suppressor cell networks, it is anticipated that tolerance, perhaps in association with microchimerism, will result in long-lasting allograft survival with little or no continued immunosuppression in man.