Immunology Faculty Member - Joren Madsen, MD

Joren Madsen, MD

Director, MGH Transplant Center
Co-Director, Center for Transplantation Sciences

Massachusetts General Hospital East
Center for Transplantation Sciences
Building 149, 13th Street, Suite 9008
Charlestown, MA 02129
Tel: 617-726-6506
Email: JCMADSEN@PARTNERS.ORG



Our laboratory studies the molecular and cellular mechanisms of transplantation rejection and tolerance with an emphasis on organ-specific differences in an alloresponse and the role of innate immunity in transplantation. Current lines of investigation include:

Heart allograft tolerance through mixed chimerism and kidney co-transplantation.
Combining bone marrow and organ transplantation to induce mixed chimerism can result in a tolerance state. However, 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 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.
We have 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 now optimizing protocols that will exploit the tolerogenic potential of the vascularized donor thymus in the host; a strategy particularly advantageous to pediatric heart transplant recipients.

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 immunosuppressive 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.

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.



Last Update: 1/23/2015



Publications

Lee, R.S., Yamada, K., Houser, S.L., Womer, K.L., Maloney, M.E., Rose, H.S., Sayegh, M.H., Madsen, J.C. Indirect recognition of allopeptides promotes the development of cardiac allograft vasculopathy. Proc Nat Acad Sci 2001 98:3276.

Uehara S, Chase CM, Kitchens WH, Rose HS, Colvin RB, Russell PS, Madsen JC, NK cells can trigger allograft vasculopathy: the role of hybrid resistance in solid organ allografts.
J Immunol 2005;175:3424-3430.

Weiss, M.J., Guenther, D.A., Mezrich, J.D., Sahara, H., Ng, C.Y., Meltzer, A.J., Sayre, J.K., Cochrane, M.E., Pujara, A.C., Houser, S.L., Sachs, D.H., Rosengard, B.R., Allan, J.S., Benichou, G., Madsen, J.C. The indirect alloresponse impairs the induction but not maintenance of tolerance to MHC class I-disparate allografts.
Am J Transplant 2009;9:105-13.

Liu w, Xiao X, Demirci G, Madsen JC, Li XC. The innate NK cells and macrophages recognize and reject allogeneic non-self in vivo via different mechanisms.
J Immunol 2012;188:2703-11.

Madariaga ML, Michel SG, Tasaki M, Villani V, La Muraglia II GM, Sihag S, Gottschall J, Farkash EA, Shimizu A, Allan JS, Sachs DH, Yamada K, Madsen JC. Induction of Cardiac Allograft Tolerance Across a Full MHC barrier in Miniature Swine by Donor Kidney Co-transplantation.
Am J Transplant 2013:10:2558-66.

Hirohashi T, Chase CM, DellaPelle P, Sebastian D, Farkesh E, Colvin RB, Russell PS, Alessandrini A, Madsen JC. Depletion of T regulatory cells promotes natural killer cell-mediated cardiac allograft vasculopathy.
Transplantation 2014 98(8):828-34.

Madariaga LM, Michel SG, LaMuraglia GM, Sihag S, Leonard DA, Farkash EA, Colvin RB, Cetrulo CL, Huang CA, Sachs DH, Madsen JC, Allan JS. Recipient-Matching of Passenger Leukocytes Prolongs Survival of Donor Lung Allografts in Miniature Swine.
Transplantation (In Press).



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