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Extended survival versus accelerated rejection of nonhuman primate islet allografts: Effect of mesenchymal stem cell source and timing |
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| Authors: | Norma S. Kenyon Melissa A. Willman Dongmei Han Rachel S. Leeman Alex Rabassa Waldo L. Diaz James C. Geary Ena Poumian-Ruiz Anthony J. Griswold Derek J. Van Booven Ryan Thompson Philip Ordoukhanian Steven R. Head Norman M. Kenyon Kenton G. McHenry Daniel R. Salomon Amelia M. Bartholomew Dora M. Berman |
| Affiliation: | 1. Diabetes Research Institute, University of Miami, Miami, Florida, USA;2. John P. Hussman Institute for Human Genomics, University of Miami, Miami, Florida, USA The Dr. John T. Macdonald Foundation Department of Human Genetics, University of Miami, Miami, Florida, USA;3. John P. Hussman Institute for Human Genomics, University of Miami, Miami, Florida, USA;4. The Scripps Research Institute, La Jolla, California, USA;5. The Scripps Research Institute, La Jolla, California, USA The Scripps Research Institute Genomics Core Facility, La Jolla, California, USA;6. Diabetes Research Institute, University of Miami, Miami, Florida, USA Department of Surgery, University of Miami, Miami, Florida, USA;7. National Center for Supercomputing Applications, University of Illinois, Urbana-Champaign, Chicago, Illinois, USA;8. Department of Surgery, University of Illinois, Chicago, Illinois, USA |
| Abstract: | Mesenchymal stem cells (MSC) have been shown to be immunomodulatory, tissue regenerative, and graft promoting; however, several questions remain with regard to ideal MSC source and timing of administration. In this study, we utilized a rigorous preclinical model of allogeneic islet cell transplantation, incorporating reduced immune suppression and near to complete mismatch of major histocompatibility antigens between the diabetic cynomolgus monkey recipient and the islet donor, to evaluate both the graft promoting impact of MSC source, that is, derived from the islet recipient, the islet donor or an unrelated third party as well as the impact of timing. Co-transplant of MSC and islets on post-operative day 0, followed by additional IV MSC infusions in the first posttransplant month, resulted in prolongation of rejection free and overall islet survival and superior metabolic control for animals treated with recipient as compared to donor or third-party MSC. Immunological analyses demonstrated that infusion of MSC from either source did not prevent alloantibody formation to the islet or MSC donor; however, treatment with recipient MSC resulted in significant downregulation of memory T cells, decreased anti-donor T cell proliferation, and a trend toward increased Tregulatory:Tconventional ratios. |
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