The long-term objective of the proposed study is to develop strategies of immune depletion and repletion which will facilitate engraftment and be applicable to human organ transplantation. This objective will be achieved by investigating in non-human primates the approaches already proven successful in rodent organ transplant experiments before applying those approaches in human clinical trials. The use of total lymphoid irradiation (TLI) will be refined in the rhesus monkey prior to renal transplantation. TLI will be used alone and in conjunction with drugs, monoclonal antibodies, and adoptively transferred effector T cells to prolong allograft survival and pig-to-monkey xenograft survival. To establish new and innovative strategies to immune modification of sensitized recipients, the alloantibody and xenoantibody responses to heart and liver grafts in rats and kidney grafts in monkeys will be characterized. Methods will include selection of antibody by class and subclass; suppression by monoclonal antibody directed against antibody forming cells, their precursors and the collaborating T-cells; and depletion of allo- or xeno-reactive antibody before transplantation established that the predominant T cell receptor gene rearrangements observed in long-lived T cell lines from human renal allografts also occur in monkeys, then monoclonal antibodies and/or effector T cells directed against these receptors will be used to prevent or treat rejection. Within the time period of the Program Project, the new and promising strategies of immune modification which are proven successful and safe in non-human primates may become the subjects of human clinical investigations.
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