Effects of Rapamycin and Donor-Specific Transfusions on Activation-Induced Cell Death (AICD) and the Induction of Tolerance to Cardiac Allografts in Miniature Swine

• Applicant: Dr. Rüdiger Hörbelt
• Subject Area: Cardiac and Vascular Surgery
• Term: from 2003 to 2004
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 5410310

Current treatment for allograft rejection requires generalized, chronic immunosuppression, which is associated with debilitating drug-specific side effects, infection, cancer and chronic rejection. The optimal way to overcome all these problems is to induce specific tolerance to donor alloantigens in the host. This would allow long-term acceptance of transplanted organs without immunosuppression, and at the same time preserve the host's ability to fight infection and malignancy. It has been established that T cells that specifically recognize the transplanted alloantigen are responsible for acute rejection and that they also contribute to chronic allograft rejection. Data emerging from prior animal studies indicate that multiple T cell-related mechanisms are involved in the induction of tolerance. According to recent rodent data, deletion of the large alloreactive T cell pool by activation induced cell death (AICD) is necessary for stable tolerance. However, this finding has not been established in a large animal system. The aim of this study is test the hypothesis that facilitating AICD will permit the induction of tolerance to a cardiac allograft in major histocompatibility complex (MHC) inbred miniature swine. We will use high dose donor specific transfusions combined with a short course of rapamycin to induce AICD of the alloreactive T cell pool. The induction of rapid and stable tolerance via this strategy would have important clinical implications.

• DFG Programme: Research Fellowships