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    Overview

    Historically, there have been two major problems in the field of organ transplantation: chronic immunosuppression and donor organ shortage.

    Tolerance

    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.

    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 have just initiated a new clinical trial with the revised regimen aiming at inducing tolerance more efficiently and safely. We are also attempting to extend our approach to deceased organ transplantation (kidney, heart and lung transplantation) using a newly developed “delayed tolerance” conditioning protocol.

    Xenotransplantation

    Another major problem is organ shortage. Currently, over 108,000 individuals need an organ, but fewer than 40,000 transplants are performed every year in the U.S. To address this unmet health care need, we are investigating the use of porcine organs for human transplantation. With recent advances in genetic modification technology, we have now achieved an over 600-day kidney xenograft survival rate in nonhuman primates with only one or two immunosuppressive medications.

    We expect to have the first human clinical trial launch in a couple of years.

    Lab Members

    Principal Investigators

    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

    Ahmad Karadagi, MD, PhD
    Toshihide Tomosugi, MD
    Ryo Otsuka, PhD
    Abbas Dehnadi, DMD

    Research Nurse

    Kerry Crisalli, RN 

    Research Technologist

    Ashley D’Attilio

    Former Members

    Grace Lassiter, MD (St. Elizabeth Hospital), Takayuki Hirose, MD (Hokkaido Univ.), Tetsu Oura, MD (Hokkaido Univ.), Kiyohiko Hotta, MD (Hokkaido Univ.), Masatoshi Matsunami, MD (Kameda General Hospital), 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)

    Research Projects

    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 was published in the New England Journal of Medicine in 2008. A new clinical trial has just begun in 2022 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. These studies are now being extended to renal transplant models.

      The Mass General Transplant Center

      is a destination for those requiring transplant, and is the only center in the region to offer adult transplantation for every organ.

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