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Research at Mass General
The Cardiothoracic Transplantation Laboratory in the Center for Transplantation Sciences (CTS) at Massachusetts General Hospital is dedicated to:
The investigations in this laboratory utilize the MHC inbred miniature swine transplant system which is unique among large animal models of transplantation. Our focus on thoracic organs is based on the fact that the immune system responds more aggressively to heart and lung allografts than to other allografts such as kidney or liver. Experimental tolerance protocols that are successful in kidney or liver recipients are typically not as effective in heart or lung recipients. We believe that organ-specific research is critical to advancing the field of heart and lung transplantation.
Joren C. Madsen, MD, DPhil Co-Director, Center for Transplantation Sciences (CTS)Senior Investigator/Head, Cardiothoracic Transplantation Laboratory, CTSDirector, Massachusetts General Hospital Transplant Center W. Gerald and Patricia R. Austen Distinguished Scholar in Cardiac SurgeryProfessor of Surgery, Harvard Medical SchoolView publicationsEmail
Deatrice Moore, Staff Assistant III to Dr. Madsen
Joren C. Madsen, MD, DPhil, received his Bachelor of Science from Brown University, his medical degree from the University of Massachusetts Medical School and a doctorate degree in immunology from Balliol College, Oxford University. Dr. Madsen completed a Massachusetts General Hospital surgical residency in 1990 and went on to train in cardiothoracic surgery at Mass General and Boston Children’s Hospital. He joined the professional staff of the Mass General Division of Cardiac Surgery in 1993. He was the surgical director of Cardiac Transplantation at Mass General between 1999 and 2006 and section chief of the Division of Cardiac Surgery between 2008 and 2011.
Currently, Dr. Madsen is Professor of Surgery at Harvard Medical School and the W. Gerald and Patricia R. Austen Distinguished Scholar in Cardiac Surgery at Mass General. He is the founding director of the Mass General Transplant Center and is co-director of the Transplantation Biology Research Center.
Dr. Madsen has served on the boards of the International Society of Heart and Lung Transplantation and the American Transplantation Society (AST), and on the editorial boards of Transplantation, American Journal of Transplantation and the Annals of Thoracic Surgery. He received the Fujisawa Basic Science Award from the AST in 2002 and in 2009 was the first surgeon to be elected president of the American Society of Transplantation.
James S. Allan, MD Senior Investigator/Co-Head, Cardiothoracic Transplantation Laboratory, CTS Associate Chief, Thoracic Surgery, North Shore Medical Center Director, Surgical Intensive Care, North Shore Medical Center Protocol Review Chair, Subcommittee for Research Animal Care, Massachusetts General HospitalAssistant Professor of Surgery, Harvard Medical School View publicationsEmail
Lucia Madariaga, MDPJ Spencer, MD
Michael LaMuragliaMatthew O'Neil
The Cardiothoracic Transplantation Laboratory leads the following research projects:
Mixed chimerism, which is achieved by combining bone marrow and organ transplantation, is meant to trick the host immune system into recognizing the donor organ as self, inducing a state of transplant tolerance. This state makes chronic immunosuppression unnecessary, thereby eliminating the associated dangers, and has been achieved in recipients of kidney, but not heart, allografts. It is well known that kidney and liver allografts are tolerance-prone while heart and lung allografts are tolerance-resistant. We have taken advantage of the tolerogenicity of kidney allografts by co-transplanting a donor kidney with the heart allograft and have achieved long-term, stable tolerance of major histocompatibility complex (MHC) mismatched heart allografts for the first time in MHC inbred miniature swine and non-human primates. We are now determining the kidney-specific cell or cell product responsible for mediating kidney induced cardiac allograft tolerance (KICAT). The ultimate goal is to utilize this renal cell or cell product instead of the donor kidney to achieve long-term, stable tolerance in patients transplanted with heart allografts alone.
Our laboratory has shown that the thymus, an organ in the chest that educates immune cells to respond only to foreign antigens, plays a critical role in achieving stable tolerance in allograft recipients. Based on this finding, we hypothesized that a state of tolerance might be achieved in heart transplant recipients if fully vascularized and functional thymic tissue from the donor was transferred to the recipient at the time of donor heart implantation. To test this hypothesis, we developed two new techniques to transplant vascularized thymic grafts along with heart allografts: the “thymoheart” allograft, which is a novel composite organ produced by implanting thymic autografts into the donor heart several months prior to organ transplantation, and the heart en bloc thymus allograft, which maintains the vascular integrity of the thymus and heart during procurement. We are currently optimizing the induction protocol for cynomolgus recipients of the heart en bloc thymus allografts. This strategy will be particularly advantageous to pediatric heart transplant recipients who have large thymii that are more easily transplanted.
Our laboratory has achieved long-term lung allograft acceptance in nonhuman primates without the need for ongoing immunosuppression. This has been accomplished through a short course of high dose calcineurin inhibitor in swine and the induction of stable mixed chimerism using donor bone marrow and an IL-6R blocking antibody in non-human primates. These results represent the only instance in which tolerance of a lung allograft has been achieved in preclinical, large animal models. Current work is aimed at optimizing these protocols for clinical use.
The concept of restoring tissue function by delivering functional cells, or engineered tissue constructs, introduced a new way of thinking for stem cell and development biologists, inspiring the goal to ultimately regenerate lost tissues. Organ engineering now takes that dream one step further to not only generate cells and tissues, but to generate whole organs that can be derived from a patient’s cells and transplanted like donor organs. The goal is to overcome donor organ shortage by being able to generate organs on demand and overcome the need for immunosuppression by using patient-derived cells. However, the immunogenicity of these constructs in unknown. In collaboration with Harald Ott, MD, we are bioengineering kidney grafts using decellularized porcine constructs reseeded with pig stem cells. They are being transplanted into MHC inbred miniature swine and the host immune response systematically analyzed
A central proposition in scientific literature is that MHC-driven T and/or B cell responses play a necessary role in CAV. However, we have utilized a novel system of semi-allogeneic cardiac transplants between parental donors and F1 hybrid recipients to provide evidence that NK cells, members of the innate immune system, also contribute to the generation of CAV in mice. This finding marks the first demonstration that NK cells participate in the chronic rejection of solid organ allografts. Recent experiments have shown that the NK cell-triggered pathway is also involved in the CAV induced by alloantibodies and viral infections. Thus, targeting NK cells may prove to be an effective way to prevent CAV in human heart transplant recipients.
We are studying how to prevent hyperacute and delayed xenograft rejection in pig-to-primate lung transplantation, which should bring us closer making lung xenotransplantation in patients a reality. Donor lungs from genetically-manipulated miniature swine that do not express the target antigen for human natural antibodies (Gal-T KO pig) but do express relevant human proteins (i.e., CD47 and CD55) will be transplanted orthotopically into baboons treated with either standard triple-drug immunosuppression or a tolerance induction protocol comprising bone marrow transplantation (mixed chimerism).
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