Our current mixed chimerism has reliably achieved long-term kidney graft survival exclusively in monkeys (60%) displaying low memory T cell reactivity against their donors prior to transplantation in cynomolgus monkeys (5-7). The presence of regulatory T cells (Tregs) capable of suppressing anti-donor inflammatory responses in vitro was consistently detected in tolerant animals. On the other hand, monkeys displaying high anti-donor memory responsiveness rejected kidney allografts in an acute fashion (6,7). Finally, it is important to note that approximately half of the long-term surviving kidney allografts succumb eventually to chronic rejection (8). These observations stress the need to improve our protocol in order to achieve tolerance to kidney and islet/kidney transplants in 100% of monkeys. Projects 1 and 2 of this program project propose a series of novel strategies designed to induce tolerance to kidney and islet/kidney allografts in monkeys. Successful tolerance induction in both of these studies rely on the basic principles that prevention/suppression of pro-inflammatory alloimmunity combined with enhancement of immune regulation will promote tolerogenesis. Project 3 is 1) to investigate the mechanisms by which the in vivo treatments described in Projects 1 and 2 influence the immune response in monkeys transplanted with allogeneic kidneys, islets or islet/kidneys and, 2) elucidate the nature of the cells, soluble factors and immunological mechanisms involved in induction and maintenance of transplant tolerance. This knowledge will help us determine how to select the appropriate donor/recipient combinations and to refine the treatments proposed in Project 1 and 2 in order to reliably achieve tolerance to kidney and islet transplants in primates. To study this, we propose the following Aims:
Specific aim 1. Investigate donor hematopoietic mixed chimerism, leukocyte recovery and deleterious alloimmune T cell responses in transplanted monkeys Specific aim 2. Investigate regulatory T cell responses associated with transplant tolerance Specific aim 3. Investigate B cell responses and their contribution to rejection and tolerance Understanding the mechanisms by which tolerance is induced and maintained in our primate transplant model should significantly expand the successful application of tolerance protocols in clinical transplantation and for the treatment of immune-mediated diseases requiring tolerogenesis of harmful memory T cells in patients such as autoimmune disorders and allergies.
Project 3 will elucidate the nature of the cells, soluble factors and immunological mechanisms involved in induction and maintenance of tolerance (indefinite survival of transplants without immunosuppression) to kidney and pancreatic islets in non-human primates. Understanding the mechanisms by which tolerance is induced and maintained in our primate transplant model should significantly expand the successful application of tolerance protocols in clinical transplantation and for the treatment of immune-mediated diseases requiring tolerogenesis of harmful memory T cells in patients such as autoimmune disorders and allergies.
|Hotta, Kiyohiko; Oura, Tetsu; Dehnadi, Abbas et al. (2018) Long-term Nonhuman Primate Renal Allograft Survival Without Ongoing Immunosuppression in Recipients of Delayed Donor Bone Marrow Transplantation. Transplantation 102:e128-e136|
|Sasaki, Hajime; Oura, Tetsu; Spitzer, Thomas R et al. (2018) Preclinical and clinical studies for transplant tolerance via the mixed chimerism approach. Hum Immunol 79:258-265|
|Smith, R N; Adam, B A; Rosales, I A et al. (2018) RNA expression profiling of renal allografts in a nonhuman primate identifies variation in NK and endothelial gene expression. Am J Transplant 18:1340-1350|
|Gonzalez-Nolasco, Bruno; Wang, Mengchuan; Prunevieille, Aurore et al. (2018) Emerging role of exosomes in allorecognition and allograft rejection. Curr Opin Organ Transplant 23:22-27|
|Smith, R N; Matsunami, M; Adam, B A et al. (2018) RNA expression profiling of nonhuman primate renal allograft rejection identifies tolerance. Am J Transplant 18:1328-1339|
|Benichou, Gilles; Prunevieille, Aurore (2018) Graft-derived exosomes. When small vesicles play a big role in transplant rejection. Am J Transplant 18:1585-1586|
|Thaiss, Cornelius C; Oura, Tetsu; Sasaki, Hajime et al. (2018) Importance of Hematopoietic Mixed Chimerism for Induction of Renal Allograft Tolerance in Nonhuman Primates. Transplantation :|
|Dehnadi, Abbas; Benedict Cosimi, A; Neal Smith, Rex et al. (2017) Prophylactic orthosteric inhibition of leukocyte integrin CD11b/CD18 prevents long-term fibrotic kidney failure in cynomolgus monkeys. Nat Commun 8:13899|
|Benichou, Gilles; Kim, James (2017) Editorial: Allorecognition by Leukocytes of the Adaptive Immune System. Front Immunol 8:1555|
|Oura, T; Cosimi, A B; Kawai, T (2017) Chimerism-based tolerance in organ transplantation: preclinical and clinical studies. Clin Exp Immunol 189:190-196|
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