AUGMENTATION OF THE TRANSFUSION EFFECT

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Blood transfusions exert a powerful and long lasting immunosuppressive effect in both man and experimental animals which is both donor specific and non-specific. This immunosuppressive effect occurs as early as 24 hours after blood administration, thus making donor specific transfusions useful in both cadaveric and living related donor transplants. Graft tolerance associated with the administration of blood is an active immunologic process involving the development of both specific and non- specific macrophage and T lymphocyte suppressor cell networks. The transfusion effect is mediated in part by eicosanoids released from the macrophages and can be augmented by low doses of cyclosporine, the administration of linoleic acid, the prostacyclin analogue Iloprost, the stable prostaglandin analogue 16, 16 dimethyl PGE2, and the lipoxgenase pathway inhibitor NDGA. Conversely, the transfusion effect is reduced or eliminated by the administration of indomethacin (a cyclooxygenase pathway inhibitor) anti-CD4 monoclonal antibodies (which eliminates a subset of suppressor inducer cells), high doses of cyclosporin and high doses of steroids. The long-term goal of the proposed studies is to further refine methodologies to augment the donor specific transfusion effect in animals which can be applied to man to achieve permanent or long-lasting tolerance to an allograft with minimal or no long-term immunosuppression. Specific components of the proposed studies include optimization of multi-modality therapy, first by defining optimal dose responses for anti-CD3 antibodies, Iloprost, NDGA, 16, 16 dimethyl PGE2, and linoleic acid alone and in combination, first in a screening model in rats and then in verification models in rats and dogs. The investigator's previous laboratory studies have led to the development of a clinical protocol for both living related donor and cadaveric renal transplants which involves the administration of donor specific transfusions, cyclosporine and ketoconazole beginning one day prior to transplant. This clinical trial will be performed concurrently and should lead to more effective, safer and less costly modes of immunosuppression in man.