Sirolimus and Thymoglobulin to Prevent Kidney Transplant Rejection

This protocol will test a novel dual agent combination therapy for its ability to prevent human renal allograft rejection. Thymoglobulin (Sangstat), a FDA-approved polyclonal rabbit-IgG antithymocyte preparation, will be given for ten days at the time of transplantation to achieve profound lymphocyte depletion. This will be paired with chronic therapy with Sirolimus (rapamycin, Wyeth-Ayerst), an oral immunosuppressant agent recently approved by the FDA. Rapamycin allows for antigen specific T cell activation but prevents T cell clonal expansion by interrupting IL-2 receptor beta-chain signal transduction. The rationale for this combination is to eliminate existing alloreactive T cell clones that could initiate a rejection at the time of transplantation, and to promote graft specific activation induced cell death (AICD) in repopulating T cells such that an allospecific T cell deficit is induced. The desired effect of this therapy is to prevent allograft rejection without the chronic use of calcineurin inhibitors or glucocorticosteroids, and in doing so, develop a regimen for transplantation that avoids most of the chronic drug toxicities inherent in the use of these two classes of immunosuppressants.

Twenty people will be evaluated in this pilot protocol. Ten will receive living donor kidney allografts and ten will receive cadaveric kidney allografts. Patients will be treated with Thymoglobulin beginning prior to graft implantation and continuing for ten days. Glucocorticosteroids will be given during the Thymoglobulin treatment to limit monocyte activation and prevent the cytokine release syndrome associated with this antibody preparation. Patients will be given Sirolimus orally beginning the day after transplantation and continuously thereafter. 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 a specific desired effect, allospecific AICD, that should promote the development of allospecific graft tolerance. This will be accomplished by assaying peripheral blood and allograft biopsies for apoptosis and peripheral blood for evidence of alloreactive T cell clone depletion.