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Transplant Surgery
Principal Investigators:
A. Benedict Cosimi, M.D.
Paul S. Russell, M.D.
Francis L. Delmonico, M.D.
Hugh Auchincloss,Jr., M.D.
Dicken S. C. Ko, M.D.
Tatsuo Kawai, M.D.
Maria Koulmanda, Ph.D.
Henry Winn, Ph.D.
Siew-Lin Wee, Ph.D.
Martin Hertl, M.D.
Gilles A Benichou, Ph.D.
Dr. Paul S. Russell instituted clinical transplantation at the MGH in April 1963, with the first kidney transplant. As it became feasible to replace successfully the function of other organs through transplantation, it became necessary to add expert staff equipped to evaluate and care for patients suffering from the terminal failure of these additional organs. At the same time, it was recognized that the challenges of replacement of different organs had much in common from one system to another, and that it was highly desirable for patients receiving any transplanted organ to be cared for by members of a seasoned team which included not only specialists in the organ system to be replaced, but also individuals well versed in the diagnosis and management of rejection and the inevitable complications of immunosuppression.. The clinical program has now expanded under the direction of the current chief, Dr. A. Benedict Cosimi, to become the only center in New England providing transplantation services for all currently available thoracic and abdominal organs for both adult and pediatric recipients.
From the beginning it was clear that, for this rapidly developing field, communication and coordination of effort is called for not only between a number of clinical specialists drawn from several different services but also between clinicians and laboratory scientists. The achievement of an optimal environment for the prompt application of the results of laboratory investigation toward the improvement of clinical practice stands as one of the most important objectives of the entire program. Personal relationships on which collaborative projects depend have been fostered by regular conferences and in the common cause of shared research programs. Such programs are also facilitated by research grants held in common by clinical and laboratory researchers, such as our Program Project grants. Since its inception, the MGH Transplantation Unit has never been without this kind of broad-based research funding from the NIH. The Program Project grants, multiple R01 research grants and significant collaborative relationships with industry now combine to support the clinical and laboratory investigations of the Transplant Unit and the additional ties with the research programs of the Transplantation Biology Research Center (TBRC).
Current research projects:
Vertical integration in the Transplantation Research programs of the MGH is in place and functioning well. Studies of the basic science of transplantation are actively pursued both in the TBRC and in the laboratories of the Transplant Unit. Exciting new findings at the basic level are translated rapidly into pre-clinical studies which are carried out as collaborative efforts between the TBRC, and Transplant Unit, and the Bone Marrow Transplantation Service. An example is the translation of findings in murine models that establishment of mixed chimerism produces long-term specific transplantation tolerance. These findings have subsequently been carried out in miniature swine as a large animal model, and in cynomolgus monkeys. The encouraging results obtained have now been extended to the first ever patient trials of tolerance induction under Dr. Delmonico’s and Dr. Ko's direction. In addition, there are a variety of other laboratories at the MGH carrying out basic research related to transplantation, including those in the Department of Medicine, the department of Pathology, and other laboratories in the Department of Surgery. Through common research seminars new findings in these laboratories also have ready access to further pre-clinical and clinical development. Clinical studies currently in progress which have developed from vertical integration of basic and pre-clinical studies include the use of monoclonal antibodies for prophylaxis and treatment of rejection, new protocols for induction of tolerance through inhibition of T cell help, studies of donor specific transfusion and the potential for inducing mixed chimerism, and the extension of bone marrow transplantation to the induction of chimerism and tolerance.
Our research efforts are directed toward solving the two major limitations to the field of transplantation which exist today: 1) chronic allograft rejection and; 2) donor organ-availability. Induction of specific tolerance would potentially prevent not only rejection, but also, the need for chronic treatment with immunosuppressive medications and their attendant complications. Xenotransplantation, utilizing miniature swine as a donor, is a major area of basic and pre-clinical research at the MGH, and will potentially provide a solution to the problem of donor organ availability.
Animal and Clinical Models:
Basic research is carried out the in Transplant Unit laboratories on White 5, as well as in the Primate laboratory and Surgical laboratories in Wellman and in the Cox 5 Immunopathology laboratories. Studies include the use of new monoclonal antibodies to specifically modify immune pathways in the rejection of transplanted organs, studies of the basic biology and immunology of pancreatic islet transplantation, studies of the basic cellular and humoral immunology of transplant reactions and studies of transplant arteriopathy.
Pre-clinical transplantation studies are carried out under Dr. Cosimi’s direction in non-human primates and are directed predominantly to the definition of clinically applicable tolerance induction therapeutic protocols for solid organ allografts. One of Dr. Dicken Ko’s efforts is to extend the approach of tolerance induction via mixed chimerism to pancreatic islet allografts in these non-human primates.
A number of studies involving pancreatic islet transplants in both mice and cynomolgus monkey models are also being pursued under the direction of Drs. Auchincloss and Koulmanda. Clinical studies of pancreas transplantation (either whole organ or isolated islets) have also been carried out at the MGH under Dr. Auchincloss’s direction. Between 1986 and 2002, approximately 65 combined kidney and pancreas transplants were performed with organ survival at one year greater than 80% and patient survival over 90%. Although these patients have remained euglycemic for many years, the use of whole organ pancreas transplantation to treat diabetes has serious limitations. Thus, clinical efforts in pancreas transplantation at the MGH have more recently shifted in emphasis to the possibility of using cellular islet transplants. The first patients began entering these clinical trials in 2001.
Other studies being intensely pursued, particularly in Dr. Paul Russell’s laboratories are related to chronic transplant rejection and “transplant arteriopathy.” The prevalence and severity of proliferative changes in the linings of arterial vessels serving transplanted organs that often appear in the course of time after transplantation has become a major concern in the field. These arteriopathic changes can be found in any transplanted organ, although they are perhaps most ominous in the case of the coronary vessels of transplanted hearts. Dr. Russell’s model employs hearts transplanted by microvascular techniques between mice according to a technique established in our laboratories. These animal subjects that are highly characterized in terms of their genetic constitution allow the study and manipulation of the rejection process under well-controlled immunogenetic circumstances.
CURRENTLY FUNDED PROJECTS:
Principal Investigator:
Hugh Auchincloss, M.D.
Tolerance: An Approach to Cardiac Allo & Xenotransplants Cell Mediated Immunity to Xenografts
We are studying the importance of the direct and indirect recognition in xenograft rejection.
Regulatory T cells Through the indirect Pathway
We are comparing the roles of direct and indirect recognition in allograft rejection
Xenogeneic Islet Transplantation
We are examining the mechanisms of rejection of xenogeneic islet transplants in primates.
JDF Center for Islet Transplantation
We are studying islet transplantation in non-human primates.
Principal Investigator:
Gilles A. Benichou, Ph.D.
Immnogenicity/Immune rejection of retinal transplants
We are studying the molecular and cellular facets of host immunity in retinal transplants. Principal Investigator:
A. Benedict Cosimi, M.D.
Tolerance: An Approach to Cardiac Allo & Xenotransplants
We are developing in non human primates a clinically applicable regimen for inducing tolerance to heart transplants.
JDF Center for Islet Transplantation
This Core Facility provides facilities and technical support for all non-human primate studies being performed by JDF investigators.
Immune Tolerance Network
We are enrolling patients with ESRD into a protocol for inducing tolerance to the renal allograft. Principal Investigator:
Francis L. Delmonico, M.D.
Immune Tolerance Network
This multi-institution clinical trial is designed to induce allograft tolerance and control of neoplasia in patients with ESRD and multiple myeloma. Principal Investigator:
Tatsuo Kawai, M.D.
Mixed Chimerism and Tolerance in Cynomolgus Monkeys
We are examining the mechanisms involved in tolerance induction by mixed chimerism. Principal Investigator:
Dicken Ko, M.D.
Mixed Allogeneic Chimerism Approach to Islet Cell Transplantation Tolerance in Cynomolgus Monkeys
We are developing a conditioning regimen that induces tolerance to pancreatic islet allografts for treatment of diabetes mellitus.
Allogeneic Hepatocyte Transplantation for the Treatment of Cirrhosis
We are evaluating the efficacy of allogeneic hepatocyte infusions for stabilization of hepatic encephalopathy. Principal Investigator:
Paul S. Russell, M.D.
Cardiac Transplant Atherosclerosis
We are evaluating the pathogenesis and methods of preventing chronic allograft vasculopathy. back to top |
