ORTHOTOPIC LIVER TRANSPLANTATION

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Fulfillment of previous grant objectives allows us to return to the laboratories to new inquiries. First, better immunosuppressive drugs will be assessed with emphasis upon: an anti-T lymphocyte agent 500-1000 times more potent than cyclosporine (FR900506), which inhibits interleukin 2 production; and deoxyspergualin, a weaker but novel immunosuppressant which acts at the macrophage level of the immune response in vitro techniques will be used to study the effects upon alloactivated T-lymphocytes and other cell populations including monocytes, the intrinsic cytotoxicity of agents to be tested, the mechanisms of immunosuppression, and the assessment of synergism with other drugs. Transplantation in rats (kidney, heterotopic heart, and liver), dogs (kidneys, liver, heart, pancreas, intestine) and baboons (kidney and liver) will be used to test dose/efficacy relations, synergism, pharmacokinetics, species and organ specific factors, and toxicity. The feasibility and value of these studies has been demonstrated unequivocally in preliminary experiments. Second, pharmacologic techniques are proposed to prevent the acute or hyperacute rejection of grafts by preformed cytotoxic or other antigraft antibodies by using prostaglandins and other modulators of the inflammatory response and by using inhibitors (platelet activating factor inhibitors, thromboxane A2 synthetase inhibitor, superoxide dismutase) of the pathophysiologic cascade set into motion by tissue injury which in turn leads to irreversible injury of the microvasculature. The test models will be pig to dog renal transplantation and heterotopic heart transplantation in presensitized rats. The astonishing ability to prevent hyperacute rejection with this approach has been unequivocally demonstrated in preliminary experiments using models. Third, the same mediators, modulators, and inhibitors will be used singly and in combination in rat and dog transplant and non- transplant models to protect livers from normothermic and hypothermic injury with the objective of prolonging the period of safe preservation. Non-transplant ischemia models already have been standardized in both species as well as a unique acetaminophen toxic model in dogs. The feasibility of the proposed therapy has been proved in preliminary studies. Taken as a whole, the work is designed to increase the safety, cost, efficiency, and applicability of all kinds of organ grafting procedures, thereby improving patient care. Advances in any of the proposed areas with any of the organs (liver, kidney, or heart should be applicable to all of the organs.