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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
Abbas Dehnadi, DVM
Kiyohiko Hotta, MD
Tetsu Oura, MD
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 Cosimi/Kawai Laboratory in the Center for Transplantation Sciences is leading the following research projects:
- Tolerance of kidney and islet transplantation via the mixed chimerism approach: The major goal of this study is to induce islet allograft tolerance by co-transplanting a kidney allograft with combined donor bone marrow transplantation
- Immunological studies of the recipients of combined kidney and bone marrow transplantation: The aim of this study is to elucidate the mechanisms of tolerance in patients who achieved renal allograft tolerance after induction of transient chimerism
- Tolerance induction via mixed chimerism approach of the heart allograft by co-transplantation of the kidney: Previous studies revealed that heart allograft tolerance was not achieved by induction of transient chimerism. However, we recently found that heart allograft tolerance can be induced even with transient chimerism when the heart-donor kidney is co-transplanted. The goal of this project is to identify an intrinsic factor in the kidney allograft that maintains heart allograft tolerance, and to develop a novel regimen to induce heart tolerance without co-transplantation of the kidney
- Deceased donor renal allograft tolerance through mixed chimerism: The goal of this study is to extend the mixed chimerism approach to tolerance induction in human recipients of deceased donor renal allografts utilizing our recently perfected “Delayed Tolerance Conditioning Protocol,” in which organ transplantation is performed first with conventional immunosppression and then with conditioning/bone marrow transplantation sometime later
- Renal allograft tolerance (living donor transplantation) induction with belatacept/ATG regimen: For wider application of our protocol, we have recently developed a novel regimen that only includes clinically available agents (belatacept and ATG). The protocol will be tested in living donor kidney transplant recipients
- Molecular basis of Mo1 LFA-1 deficiency: These studies are evaluating the in vitro effects of mAb 107 (anti-CD11b) on ischemia reperfusion injury in a non-human primate model
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.