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The Cosimi/Kawai Laboratory in the Center for Transplantation Sciences (CTS) at Massachusetts General Hospital focuses on allograft tolerance induction (the successful transplantation of an organ or tissue without immunosuppression) in nonhuman primates and humans, with the goal of developing safe and reliable tolerance-inducing regimens for clinical transplantation.
Short-term results following organ transplantation have been significantly improved by the use of increasingly effective immunosuppressive agents. However, their chronic use results in significant morbidity, especially from an increased incidence of cardiovascular disease, infection, malignancies, de novo diabetes and other metabolic disorders.
Additionally, the effects of current therapeutic protocols to regulate the immune system often do not prevent the development of chronic rejection, despite their administration being pushed to toxic levels.
Because of this, induction of tolerance, defined as the absence of destructive immune responses to a transplanted tissue without ongoing immunosuppressive therapy, remains the ultimate goal of organ transplantation.
Since the 1950s, numerous strategies for induction of tolerance have been developed in small animal models, but none of these studies has ever successfully translated to large animal models until our laboratory reported a nonmyeloablative conditioning regimen that consistently induced renal allograft tolerance in nonhuman primates (NHP) via a mixed chimerism approach, a state induced by bone marrow transplantation where host and donor cells exist without any rejection (Kawai, T et al. Transplantation 1995).
Our laboratory subsequently applied our approach in human leukocyte antigen (HLA)-mismatched kidney transplantation, and renal allograft tolerance was achieved with the longest kidney allograft survival now exceeding 12 years without any immunosuppression. This is a seminal translation of an observation, first made in mice to a preclinical NHP model, then to the first reproducibly successful induction of tolerance of renal allografts in humans that was reported in the New England Journal of Medicine in 2008 and 2013.
We are now attempting to extend our approach to deceased organ transplantation (kidney, liver and pancreatic islets) using a newly developed “delayed tolerance” conditioning protocol.
A. Benedict Cosimi, MD
Senior Investigator/Co-Head, Cosimi/Kawai Laboratory, Center for Transplantation Sciences (CTS)
Chief Emeritus, Division of Transplantation, Massachusetts General Hospital
Claude E. Welch Distinguished Professor of Surgery, Harvard Medical School
Tatsuo Kawai, MD, PhD
Senior Investigator/Co-Head, Cosimi/Kawai Laboratory (CTS)
A. Benedict Cosimi Chair in Transplant Surgery, Massachusetts General Hospital
Professor of Surgery, Harvard Medical School
Postdoctoral Research Fellows
David Ma, MD
Takayuki Hirose, MD, PhD
Abbas Dehnadi, DMD
Kerry Crisalli, RN
Svjetlan Boskovic, MD, Ognjenka Nadazdin, MD, Yohei Yamada, MD (Keio University), Aki Aoyama, MD (Kyoto University), Soyoung Lee, MD (University of Pittsburgh Medical Center), Derek Klarin, MD (Mass General), Toru Murakami, MD (Tokyo Women’s Medical University), Takanori Ochiai, MD (Tokyo Medical and Dental University), John Mercer, MD, Ichiro Koyama, MD (Tokyo Women’s Medical University), Nahel Elias, MD (Mass General), Hiroshi Sogawa, MD (University of Pittsburgh Medical Center), Gregory Abrahamian, MD (University of Texas)
The goal of our research is to establish a clinically-feasible protocol to induce allograft tolerance and develop a reliable immunosuppressive regimen to prolong survival of kidney xenografts from genetically modified pigs. The approach for tolerance induction has already been extended to clinical human kidney transplantation and what to be identified in NHP studies will continuously be translated to clinical trials. Studies on xenotransplantation have been performed in collaboration with eGenesis. We have already achieved over 250 day kidney xenograft survival without any rejection and will continue to improve graft survival by modification of immunosuppressive protocols and improving the efficacy of pig gene modification.
The Cosimi/Kawai Laboratory in the CTS is leading the following research projects:
- Bcl-2 inhibition to induce hematopoietic chimerism without myelosuppression: For wider clinical application of our approach for tolerance induction, it is imperative to avoid the severe myelosuppression associated with the current conditioning regimen, improve the levels and consistency of mixed chimerism, extend the applicability to deceased donor transplantation and clarify the mechanistic pathways of tolerance induction after only transient hematopoietic chimerism. We have identified a novel strategy that addresses these requirements by using a pro-apoptotic B cell lymphoma-2 (Bcl-2) inhibitor. Our preliminary NHP results provide promising observations that the FDA-approved Bcl-2i, ABT-199 (Venetoclax),12,13 along with costimulatory blockade, significantly promotes hematopoietic chimerism without myelosuppression and achieves long-term immunosuppression-free renal allograft survival. Furthermore, we are now pursuing to develop hematopoietic chimerism even without any genotoxic treatments such as radiation or chemotherapeutic drugs
- Clinical trial for tolerance induction in HLA mismatched kidney transplant recipients: Our first clinical trial of kidney allograft tolerance induction in recipients of HLA-mismatched transplants was initiated in 2003. The report of the first five patients enrolled was published in the New England Journal of Medicine in 2008 (Kawai T, et al: HLA- mismatched renal transplantation without maintenance immunosuppression. New Eng J Med). A new clinical trial will be resumed in 2020 in collaboration with ITBMed
- Transplantation of kidney xenograft: These studies have been conducted in collaboration with eGenesis. We so far achieved >250 day survival of a xenograft without any rejection or proteinuria from a pig with triple knock-out of carbohydrate genes (GAL, CMAH and B4) and >10 human gene transduction. Our current research goal is to develop a clinically feasible immunosuppressive regimen along with the best gene modifications for clinical application
- Studies to control ischemia/reperfusion injury: We have shown that the anti-CD11b mAb107 developed in our laboratories markedly inhibits ischemia reperfusion injury in a non-human primate model (Dehnadi, et.al.: Prophylactic orthostatic inhibition of leukocyte integrin CD11b/CD18 prevents long-term fibrotic kidney failure in cynomolgus monkeys. Nat Commun. 2017). These studies are now being extended to renal transplant models
Center for Transplantation Sciences
The Center for Transplantation Sciences (CTS) at Massachusetts General Hospital conducts critical research to increase the success rates of transplantation and meet the growing demand for organ and bone marrow transplantation.