Reproducible, long-term islet allograft acceptance and insulin independence are no longer exceptions in the setting of pre-clinical and clinical islet cell transplantation. The critical importance of steroid-free immuosuppression has been dramatically proven, and one of the major challenges facing the field today concerns definition of protocols that obviate the need for life-long immunosuppression (tolerance induction). Although it would be ideal to establish donor specific tolerance prior to islet transplantation, the current limitation to cadaveric pancreas donors as a source of islets necessitates that we continue to pursue approaches that can concomitantly enable islet engraftment and establishment of tolerance. Clinically, intrahepatic islet transplantation enables relative ease of infusion and physiological insulin delivery Post- transplant. It is often suggested that the intraportal route may also provide an immunological advantage to islets, as previous studies in rodent models have described this route of antigen delivery as being tolerogenic. Furthermore, cotransplantation of islets with cells that can deliver negative signals to the immune system has proven effective in preventing islet rejection and inducing tolerance in rodents. Neither of these approaches has been fully studied in larger animal, pre-clinical models, although several groups have attempted tolerance induction via intravenous transplantation of donor hematopoietic cell (HC) populations. We plan to test the hypothesis that co-transplantation of islets into the liver with potentially tolerogenic hematopoietic cells and/or mesenchymal stem cells (MSC) will enhance islet and HC engraftment by: 1) establishing a microenvironment that facilitates HC engraftment and the establishment of chimerism and 2) providing an intraportal milieu that is conducive to the induction of regulatory cells, thus attaining both central and peripheral tolerance. Intravenous infusion of MSC may also provide signals that enhance donor HC engraftment, thus resulting in chimerism and ultimately, tolerance. Our goal is to develop protocols that are applicable to the current setting of cadaveric pancreatic islet transplantation and. subsequently, to incorporate our results with those from project 2, to design and test protocols that will enable tolerance induction prior to transplantation of insulin producing tissue. We will use the information gained from our ongoing non-human primate studies to define the most promising combination of immunointervention agents and HC (costimulatory blockade with anti-CD154 and/or anti-B7, T cell depletion with ATG, rapamycin, fludarabine) to be tested in these intraportal and MSC protocols.
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