The Division of Transplant Immunology is both an independent entity and a major component of Beth Israel Deaconess Medical Center's Transplant Center. The Division employs 6 research faculty, 12 research fellows and 3 research technicians. The Division serves a research, not clinical, function.
The overarching research goal of the Division is to map a pathway to create immune tolerance in the clinic for patients in need of organ or islet transplants. The T cell response to MHC mismatched allografts includes both the usually large CD4+ and CD8+ pool of graft destroying effector T cells and a much smaller pool of graft protecting suppressor of regulatory T cells. The outcome of the allograft response, rejection or tolerance, is determined by the nature of the T cells, effector or regulatory, that are ascendant in the allograft recipient. The functional ascendancy of the effector T cells causes rejection while the functional ascendancy of regulatory T cells in an immunosuppressive drug-free host creates tolerance. In addition to the numeric superiority of effector T cells, effector T cells respond to antigens with a far greater speed than regulatory T cells. The allograft response has been crafted to swiftly reject the allograft. In the absence of effective immunosuppression, rejection is the almost inevitable outcome. Tolerance is even more difficult to achieve than long-term drug-free engraftment. A treatment regimen that exclusively targets only recently activated cytopathic donor reactive T cells and spares regulatory T cells might prove to be an exceptionally potent and selective means of fostering long-term engraftment and tolerance. This is our goal.
To date, there has been a failure to identify a tolerizing regimen that appears safe enough for broad clinical application that works in every model system. It seems likely that the most appealing of today's candidate putative tolerizing regimens for human testing will, at best, tolerize some but not all transplant recipients. Needed are powerful surrogate markers for tolerance, markers that identify organs that will elicit signals that will confound tolerance induction and markers that forewarn of impending rejection. As Type 1 diabetes is the primary disease for many transplant recipients, the Division also is seeking a means to restore self-tolerance to islets in Type 1 diabetes patients.
To this end, members of the Division study 1) basic T-cell immunobiology; 2) the biology of antigen-presenting cells; and 3) the cellular and molecular basis of rejection and tolerance. To spur translation of basic science concepts into a potentially clinical execution we have developed unusual strengths in several areas. First, we are developing mice in which CD4+ T-cells that are committed to any of the distinctive helper effector populations, e.g., Th1, Th2, regulatory T-cells and Th17 cells, can be identified on the basis of subset select expression of distinctive chromophores. This allows us to readily examine the role of these subsets in rejection and tolerance induction. Moreover, we are able to easily profile these CD4+ subset cells to further examine their molecular and functional attributes. Second, under the leadership of Dr. X.X. Zheng, we are adept at creating new protein-based therapeutics. In this effort, we often develop proteins in which an agonist or antagonist cytokine or the extracellular portion of a cell surface protein is fused to IgG heavy chains. The Ig domain allows for easy purification and a very long circulating half-life in vivo. Production for one particular Ig-based treatment regimen has shown great promise in preclinical models of transplantation and new onset autoimmune diabetes. The NIH is now producing therapeutic grade proteins for our clinical trials in new onset diabetes and islet transplantation. Third, we have used transcriptional and, more recently, proteomic profiling methods to identify molecular signatures for rejection and tolerance. This analysis has been extended into NIH-funded clinical trials in the hope that a truly incisive and individualized approach to the care of transplant patients will emerge.
In addition to Division Co-Chiefs Drs. Terry B. Strom and Laurence Turka, the Division includes five other faculty. Dr. Xian C. Li, an Assistant Professor of Medicine, has made several critically and widely heralded observations concerning the vital role of the apoptotic death of aggressor T-cells in creating immune tolerance to MHC unmatched transplants. More recently Dr. Li has demonstrated the importance of natural killer cells to the induction of transplant tolerance-they act by destroying highly immunogenic donor antigen-presenting cells. Dr. X.X. Zheng, an Assistant Professor, is internationally renowned for his ability to design novel protein therapeutic molecules. Dr. Wenda Gao, an Instructor, has created mice in which T-cell subsets are color coded. Dr. James Kenny, an Instructor, has become a notable expert in the biology of antigen presenting T-cells. Each of the faculty members receive substantial extramural support. Dr. Wei Yang, an Instructor, is an expert in the structural biology of proteins.