Induction of Donor Specific Immunologic Hyporesponsiveness With Thymoglobulin, Sirolimus and Donor Bone Marrow Infusion

This protocol will evaluate the combination of Thymoglobulin (Sangstat), sirolimus and donor bone marrow infusion for its ability to induce a state of donor specific hematopoietic chimerism and immune hyporesponsiveness within the context of renal transplantation. Thymoglobulin (Sangstat), a FDA-approved polyclonal rabbit-IgG antithymocyte preparation, will be given for up to ten days at the time of transplantation to effect lymphocyte depletion. This will be combined with sirolimus (rapamycin, Wyeth-Ayerst), an oral immunosuppressant agent recently approved by the FDA. Sirolimus allows for antigen specific T cell activation but prevents T cell clonal expansion by interrupting IL-2 receptor beta-chain signal transduction. Donor bone marrow will be administered seven days following transplant. Patients demonstrating six months of rejection free graft survival will have their sirolimus withdrawn over three months beginning at the sixth month anniversary of the transplant.

Twenty people will be evaluated in this pilot protocol. Approximately ten will receive living donor kidney allografts and the remaining patients will receive cadaveric kidney allografts. Patients will be treated with Thymoglobulin beginning prior to graft implantation and continuing for approximately ten days. Glucocorticosteroids will be given during the first Thymoglobulin treatment to limit monocyte activation and prevent the cytokine release syndrome associated with the initial administration of this antibody preparation. Patients will be given sirolimus orally beginning the day after transplantation and continuously thereafter. Donor bone marrow will be administered seven days following transplantation. Patients will then be monitored for evidence of allograft rejection using standard functional parameters and protocol allograft biopsies. In addition, patients will be followed for specific desired effects, including a transient state of donor hematopoietic mixed microchimerism and allospecific AICD. Both of these are expected to promote the development of allospecific graft tolerance. This will be accomplished by assaying peripheral blood and allograft biopsies for apoptosis and the peripheral blood for evidence of alloreactive T cell clone depletion and donor chimerism.