Chronic immunosupression in clinical transplantation is associated with morbidity and mortality. Induction of recipient unresponsiveness to donor antigens would decrease requirements for immunosuppression and reduce associated complications. A model of specific unresponsiveness has been developed in animals immunosuppressed with ALS and injected with donor bone marrow that prolongs the survival of skin allografts in mice and renal allografts in outbred dogs and rhesus monkeys. Objectives of the present application are (1) define the role of the histocompatibility complex in the induction of unresponsiveness utilizing either donor marrow or specific or nonspecific blood transfusions as antigen (2) characterize the cell(s) in marrow responsible for unresponsiveness (3) isolate and characterize the biological activity of suppressive factors in influencing unresponsiveness (4) undertake a clinical trial of induction of unresponsiveness in recipients of cadaveric or living-related transplants using ATG and donor bone marrow (5) develop assays for early detection of rejection in transplant patients. The genetic influence on unresponsiveness will be studied in congenic mice that differ at defined regions of the H-2 complex. Mice will be given ALS and either donor marrow or donor specific or nonspecific blood and immune reactivity will be studied by in vivo and in vitro assays. Cells contained in a marrow fraction shown to induce unresponsiveness will be characterized by examining surface markers and by their ability to respond in immune reactions. Somatic cell hybridization techniques will be used to obtain hybridoma cell lines of suppressor T cells derived from ALS treated mice given blood transfusions. Supernatants from cell cultures will be assayed for suppressive activity. Clinically, the induction of unresponsiveness will be performed in patients receiving either cadaver kidneys or living-related kidneys from one haplotype mismatched, high MLC positive donors. Patients will be followed serially for helper/suppressor T cell ratios and lymphocyte responses to polyclonal antigens and to donor specific and nonspecific antigens in an effort to identify the state of specific unreponsiveness. For the development of assays for detection of rejection, immunoglobulins shed from renal tubules and urinary CRP of transplant patients will be studied. A sensitive clinically applicable assay that will detect rejection before it is evident clinically should improve treatment of rejection and prevent loss of grafts.
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