Repopulation of Liver Allografts by Recipients

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DESCRIPTION (provided by applicant): Successful liver transplantation can be performed across major histocompatibility complex (MHC) disparities in a number of strains combinations, and clinical studies have shown that immunosuppression can be completely withdrawn in some liver allograft recipients without adverse effects. Regeneration of adult liver is sufficiently robust to permit successful transplantation of reduced size liver grafts. Interestingly, the incidence of rejection and dose of maintenance immunosuppression may be diminished in recipient of partial liver transplants compared to standard whole liver allograft. Defining the mechanisms which create such a privileged immunological environment is relevant to clinical transplantation. Recent studies have suggested that bone marrow stem cells might possess a much broader differentiation potential than previously appreciated. These perplexing observations have led to the hypothesis that hematopoietic stem cells (HSCs) might be able to repair damaged tissue throughout the body. Our central hypothesis is that repopulation of cellular compartments in the hepatic allograft with recipient-derived progenitor cells is promoted by the increased regenerative stimulus of partial hepatic allografts, and that hepatic regeneration involving recipient stem cells is a key mechanism resulting in a chimeric liver and long term acceptance. We speculate that immunosuppression may influence the repopulation of liver allografts adversely. Using rat orthotopic whole and partial (50%) liver transplantation models, the mechanisms in which recipient MHC-positive hepatocytes appear in liver allografts after transplantation will be identified, the difference in repopulation of liver allografts between rejection and acceptance models will be compared, the role of Kupffer cells in repopulation of liver allografts will be determined, and the influence of immunosuppression on donor repopulation will be determined. Our studies may provide new insights into the mechanisms which promote tolerance and regeneration after liver transplantation and will provide the basis for the development of novel therapies.