The common theme which binds this Program Project together is the concerted effort to develop improved means of regulating the immune responses of human transplant recipients. Patients receiving cadaveric and living-related renal allografts, hepatic allografts and cardiac allografts are studied. In Project I T-cell lines are established from needle biopsies of rejecting transplants and the cell phenotypes, functions and specificities determined. The observation that a limited number of clonotypes predominate in graft rejection episodes is exploited to produce clonotypic antibodies reactive with the products of the predominant T-cell receptor V beta genes in order to specifically eliminate or suppress the selected clonotypes. In Project II suppressor T-cells obtained from experimental kidney and liver allograft recipients or generated in vitro using alloreactive cells from grafts as stimulators are characterized in vitro and are used in adoptive transfer experiments in attempts to reverse allograft rejection or induce tolerance in non-human primates. ln Project III the soluble factors (cytokines) produced by lymphocytes and monocytes during the allograft response are studied. Once the dynamics of cytokine production in the allograft situation and its functional consequences are known, means of modifying the course of transplant rejection with them or their inhibitors are investigated. In Project IV the interaction of T-cells with cells of the human cardiac microenvironment are studied. Mechanisms of T-cell activation during human cardiac allograft rejection are defined in order to specifically interrupt them thus preventing graft rejection. In Project V strategies of immune depletion including total lymphoid irradiation and removal of alloantibody are applied to a non-human primate renal allograft model. Monoclonal antibodies and effector T-cells directed against the predominant T-cell receptor on cells from rejecting grafts are used to prevent or treat rejection in rhesus monkeys. The new and promising strategies of immune modification proven successful and safe in non-human primates will be used in human clinical trials. The effort to specifically and predictably alter host immune function will require close collaboration between clinical and basic scientists. Investigators from the Duke Immunology, Surgery, Pathology, Medicine and Radiology Departments will participate in this Program Project.
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