Induction of specific immunologic tolerance is an ultimate goal of organ transplantation. Based on the conditioning regimen developed in our laboratory by decades-long research in nonhuman primates (NHP), we have now successfully achieved renal allograft tolerance in HLA mismatched human kidney transplant recipients via the mixed chimerism approach. However, limitations of this approach have been its inapplicability for deceased donor transplantation and the inability to induce tolerance of non-renal organs/cells. To extend this approach to deceased donor transplantation, we recently developed a novel strategy of """"""""delayed tolerance"""""""" induction, where kidney transplantation is performed first with conventional immunosuppression, followed by conditioning and donor bone marrow transplantation at a later date. In our preliminary NHP investigations, several barriers to consistent tolerance induction with this novel approach have been identified including higher alloreactive memory T cells (Tmem) and inflammatory responses. In order to develop a consistently reliable conditioning regimen for clinical application to deceased donor kidney recipients, it is essential to identify additional modalities to effectively mitigate inflammatory and Tmem responses without increasing morbidity in the recipients.
Aims 1 and 2 of this project are, therefore, designed to evaluate novel anti-inflammatory agents (anti-IL6R mAb and alpha1 antitrypsin) and strategies to overcome Tmem responses (costimulatory blockade and B cell depletion). This Project's goals also include extension of the applicability of our approach to organ/cell transplantation other than the kidney. This appears to be possible via the novel strategy of co-transplantation of the kidney with less tolerogenic organs/cells. Our studies have shown that the kidney allograft plays a critical role for induction and maintenance of tolerance of the co-transplanted organ/cells.
Aim 3 of the current study is thus designed to induce islet allograft tolerance by co-transplantation of islets and the kidney. While Project 2 will pursue islets allograft tolerance in living donor transplantation. Project 1 will develop the strategy to induce islet allograft tolerance in deceased donor transplantation. Since islets are especially susceptible to inflammatory and Tmem responses, we will incorporate novel modalities to be identified in Aims 1 and 2 into the conditioning regimen for induction of islet allograft tolerance. Finally, mechanisms by which (transient) mixed chimerism and the renal allograft induce islet allograft tolerance, will be fully investigated in collaboration with Project 3.

Public Health Relevance

Successful induction of allograft tolerance has been achieved in HLA mismatched human kidney transplant recipients via mixed chimerism. This research proposal is directed to identify novel modalities to extend our mixed chimerism approach to a much wider population of human allograft recipients and to islet allograft tolerance. Our NHP model has been proven highly relevant to clinical organ transplantation and observations from these studies should be directly transferrable to clinical application.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Program--Cooperative Agreements (U19)
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Special Emphasis Panel (ZAI1)
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Massachusetts General Hospital
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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
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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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