In pilot clinical trials, 7 patients with non-Hodgkin's lymphoma (NHL) or acute myelogenous leukemia (AML) were conditioned with total lymphoid irradiation (TLI) and anti-thymocyte globulin (ATG), and given HLA-matched 'mobilized' blood stem-cell transplants, and four patients with end state renal disease (ESRD) conditioned with the same regimen were given HLA-mismatched donor CD34+ selected blood stem cell and kidney transplants. All of the NHL and AML that entered in partial or complete remissions developed full chimerism; acute GV/HD was observed in only one patient and none have had a tumor relapse. Three of four kidney transplant patients developed transient (three months) mixed chimerism without GVHD, and immunosuppressive drugs were completely withdrawn from two patients to assess development of immune tolerance at the end of one year. We propose to test the hypothesis that the development of sustained chimerism will result in host immune tolerance to donor alloantigens in 15 HLA-matched kidney transplant patients given donor 'mobilized' blood stem cell transplant. Tolerant patients will be withdrawn from immunosuppressive drugs. In addition, we propose to study in vitro tests of immune cell tolerance to host and donor alloantigens regulatory T cells, and immune competence to viral and bacterial antigens in patients withdrawn from immunosuppressive drugs. We hypothesize that immune tolerance will develop in these groups preventing organ graft rejection and/or GVHD without the development of severe immunodeficiency. Regulatory NK T cells that are markedly increased amongst all reconstituted T cells after TLI and ATG are theorized to facilitate tolerance of donor versus host and host versus donor alloantigens.Methods for testing donor versus host and host versus donor immune tolerance in vitro include the mixed leukocyte reaction and associated cytokine secretion and cell-mediated lympholysis. Sorted regulatory T cell function will be tested in these arrays. Tests of immune competence include autoantibody and T cell proliferative responses to viral and bacterial antigens.
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