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, CTS
Director, Massachusetts General Hospital Transplant Center
W. Gerald and Patricia R. Austen Distinguished Scholar in Cardiac Surgery
Professor of Surgery, Harvard Medical School
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 Hospital
Assistant Professor of Surgery, Harvard Medical School
Lucia Madariaga, MD
PJ Spencer, MD
The Cardiothoracic Transplantation Laboratory leads the following research projects:
Heart allograft tolerance through mixed chimerism and kidney co-transplantation
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 large animals. We are now testing the hypothesis that amplifying the contributions of host regulatory T cells in heart allograft recipients undergoing mixed-chimerism conditioning will achieve long-term, stable tolerance without the need for kidney co-transplantation.
Heart allograft tolerance through vascularized thymus co-transplantation
Our laboratory has shown that the host thymus, the organ in the chest where immune cells mature and become specialized, plays a critical role in achieving rapid and 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 novel 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 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.
Lung allograft tolerance in miniature swine and non-human primates
Our laboratory has achieved long-term graft acceptance without the need for ongoing immunosuppression in a fully mismatched swine lung transplantation model. This has been accomplished using two distinct protocols: by means of a short-term, high-dose course of tacrolimus, an immunosupressive drug, and through the induction of stable mixed chimerism. Such tolerance is highly influenced by the state of innate immune activation in the recipient at the time of transplantation. Current efforts in swine are directed toward understanding and mitigating the detrimental effects of innate immune activation on tolerance induction.
In non-human primates, we have developed a technique to induce long-term graft survival without ongoing immunosuppression using a complex protocol that involves bone marrow transplantation and the use of an IL-6R blocking antibody. These data represent the only instance in which tolerance of a lung allograft has been achieved in a primate species. Current work is aimed at optimizing this protocol for clinical use.
Natural killer (NK) cells in cardiac allograft vasculopathy (CAV)
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.
Whole organ bioengineering
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.
Our research in transplantation has led to many important milestones with the goal of building replacement organs. Potential cell candidates have been derived from adult tissue biopsies and differentiated into some of the required cell types such as cardiomyocytes, endothelial cells, pneumocytes and epithelial cells. Culture conditions have been developed to induce the assembly of these cells into functional tissue constructs. In collaboration with Harald Ott, MD, we are now constructing grafts that mirror the complexity of a whole, human size organ.
Pig-to-primate heart and lung xenotransplantation
We are collaborating with David H. Sachs, MD, and Kazuhiko Yamada, MD, in studies aimed at preventing hyperacute and delayed xenograft rejection, which should bring us closer to xenotransplantation in patient care. Ultimately, donor hearts and lungs from genetically-manipulated miniature swine that do not express the target antigen for human natural antibodies (Gal-T KO pig) will be transplanted orthotopically into baboons treated with either standard triple-drug immunosuppression or a tolerance induction protocol comprising bone marrow transplantation (mixed chimerism) and/or en bloc vascularized donor thymus transplantation.
MGH Hotline 12.3.10 Members of the MGH Transplant Center gathered in the Bigelow Amphitheater Nov. 17 to hear Joren Madsen, MD, DPhil, director of the MGH Transplant Center; Jay A. Fishman, MD, associate director of the center; and Debra J. Doroni, MBA, executive director of the center and the Department of Surgery, unveil the Transplant Center's new strategic plan.
After more than two decades of leading the MGH Transplantation Biology Research Center (TBRC), David H. Sachs, MD, is stepping down from his role as director.