TOLERANCE INDUCTION TO PRIMATE ISLET ALLOGRAFTS

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. This project's goal is to develop novel, clinically relevant strategies to permit islet allograft acceptance. This will be addressed using agents with reduced toxicities, with the objective of achieving durable allograft acceptance without long-term immunosuppression (transplantation tolerance). We have successfully evaluated LEA29Y, a novel immunomodulatory reagent, to replace tacrolimus and protect allogeneic islets in a pre-clinical primate model. Results suggest that LEA29Y is a potent immunosuppressant that can effectively prevent rejection in a steroid-free immunosuppressive protocol, leading to marked prolongation of islet allograft survival in our pre-clinical model. We evaluated the effectiveness of a chimeric anti-human CD40 monoclonal antibody, Chi 220, alone and with LEA29Y. The combination of LEA29Y and Chi220 dramatically facilitated long-term survival of islet allografts. This is encouraging, as LEA29Y is able to act in synergy with either of two agents, sirolimus and Chi220. Additional ongoing drug regimen optimization experiments will address the outcome of replacement of sirolimus with yet another drug, mycophenolate mofetil (MMF). Under Aim 2, we have made progress toward developing a clinically acceptable regimen for the production of long-term stable hematopoietic chimerism as a means of achieving tolerance to transplanted islets. We have successfully optimized a leukopheresis-based protocol in non-human primates that leads to durable hematopoietic chimerism (100 days). Due to our laboratory work involving chimerism and MHC compatibility in mice, we believe use of MHC-defined animals combined with this improved regimen for achieving stable chimerism will be the critical elements necessary to achieve true long-term islet allograft function in this preclinical model. Presently, little is known about Rhesus MHC and tests need to be developed to define and screen our available non-human primate population for these. Once research advances to the level of clinical studies, MHC can be readily tested in human donor-recipient subjects, and outcomes correlated with the degree of matching