STRATEGIES FOR LARGE SCALE ISLET REPLACEMENT

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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. In this report period, no further islet mass or anatomic site experiments have been done due to the desire for a more optimal biologic immunosuppressive regimen. In search of a more clinically relevant, less toxic regimen, primates were transplanted allogeneic islets under cover of anti-LFA-1 monoclonal antibody-based therapy with very promising results. Anti-LFA-1 has proven to be a very potent immunosuppressant in our preclinical islet transplant model, making the case for its use in clinical trials. More promising though has been the recent use of a purely biologic regimen, anti-LFA-1 mAb and belatacept alone, resulting in immediate reversal of diabetes and islet survival for 367, 223, 373, 73 and 269 days. This biologic regimen promises to be a clinically relevant, tolerable regimen with potential for translation into the clinic. Additionally, we have investigated the use of 3A8, a non-depleting mouse monoclonal antibody targeting CD40. Animals transplanted allogeneic islets under cover of 3A8, basiliximab and sirolimus had graft survivals of 155, 312, 208, 120, 45 days, establishing the potential of blocking the CD40 pathway in a non-depleting fashion in transplantation. Future plans include the testing of recombinant anti-CD40 antibodies for better characterization of CD40-blockade in our islet model and transplantation, and using anti-CD40-based biologic regimens to establish preclinical data for translation into the clinic.