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Research

Transplantation and Immunology Research


Mission:

The Division of Transplantation is dedicated to building upon a solid foundation of basic, translational, and clinical research in order to define and develop the next generation of high-quality, comprehensive, cost-effective transplant programs.

Research Programs:

• Transplant rejection
• Allograft acceptance and transplant tolerance.
• Novel immunologic strategies for islet cells transplantation
• Cellular transplantation.
• New immunosuppressive compounds.


Research Interests:
• Gregg A. Hadley, Ph.D: 1) The immunologic mechanisms of renal allograft rejection and graft-vs-host disease pathology, and the development of novel therapeutic strategies for intervention in these processes, 2) Use of nanotechnology to measure immunomodulatory analytes in real time in organ transplant reipients, and 3) Development of novel processes to enable transplantation of pancreatic islet xenografts into human diabetics,

• Ronald Pelletier, MD: 1) the immunobiology of graft acceptance and the role of alloantibodies in allograft pathobiology, and 2) the relationship between cellular and humoral donor-specific immunologic recognition and post-transplant outcomes.

• Ginny Bumgardner MD, PhD: continues her investigations in transplant immunobiology, using experimental models of pancreatic islet and hepatocyte (liver cell) transplantation.

• Amer Rajab, MD, PhD: the development of novel strategies to enable transplantation of pancreatic islets into non-human primates, and the development of novel strategies for successful transplantation of islet xenografts in the non-human primate model.

• Kenneth Andreoni, MD: 1) development of mathematical models for unbiased prediction of tissue typing results to facilitate national sharing of cadaver kidneys, 2) New anti-rejection drugs, and 3) antibody-mediated injury to liver and kidney grafts

Accomplishments in Research:
• Gregg A. Hadley, Ph.D. serves as Deputy Director of Research in the Comprehensive Transplant Center. He leads a research program focused on defining mechanisms of chronic tissue injury following transplantation, and the development of novel therapeutic strategies for intervention in these processes.

• Dr. Ronald Pelletier continues the division’s investigations into the immunobiology of graft acceptance and the role of alloantibodies in allograft pathobiology. Our recent studies addressing transplantation tolerance suggest that allograft acceptance may evolve through a series of mechanisms involving TGFb and foxP3 regulatory cells. These mechanisms are associated with donor-reactive alloantibodies and pathology within the grafts, and do not lead to true transplantation tolerance, despite the ability to accept donor matched skin allografts. Our ongoing studies of the role of alloantibodies in transplantation reveal that alloantibodies are not necessarily directed at MHC molecules, but are also directed at tissue associated and tissue-specific molecules. Using new experimental assays for alloantibody detection, our studies have further revealed that some, but not all, of these antibodies are complement-fixing. Investigational studies focusing on humoral allograft rejection in an animal model are designed to carefully characterize the acute inflammatory events leading to Ab-mediated graft damage. We hope to define stages in the process that offer opportunities for therapeutic intervention to ameliorate graft damage.

• Translational Research in Immunologic Recognition and Post-transplant Outcomes. Dr. Ronald Pelletier continues his translational research (basic, tissue typing, and clinical) investigating the relationship between cellular and humoral donor-specific immunologic recognition and post-transplant outcomes. Efforts are now under way to foster living donor/recipient pair exchanges to enable increasing numbers of patients to obtain a lifesaving kidney transplant. Additionally, methods for removing circulating alloantibodies in sensitized recipients to permit safe organ transplantation continue to be investigated.

• Transplantation Immunobiology. Dr. Ginny Bumgardner continues her investigations in transplant immunobiology, using experimental models of pancreatic islet and hepatocyte (liver cell) transplantation. Dr. Bumgardner’s lab-based research focuses on basic mechanisms of alloimmune mediated hepatocyte injury. She introduced the functional hepatocyte transplantation model using transgenic hepatocytes to study the in vivo immunobiology of allogeneic hepatocellular transplantation in 1998. Published work demonstrates that allogeneic hepatocytes are vulnerable to cell-mediated as well as alloantibody mediated parenchymal cell damage. Her studies using this model in comparison to genetically matched islet transplant and heart transplant have demonstrated the importance of tissue (parenchymal cell type) in determining the phenotype and effector mechanisms comprising alloimmune responses after transplantation. Work from her lab has demonstrated that allogeneic liver parenchymal cells stimulate the maturation of CD4-independent and CD4-dependent allospecific CD8+ cytolytic effectors (allo-CTLs). This pathway is important, because it can cause transplant tissue damage, either early or late after transplant, and interferes with the induction of transplantation tolerance. These CTL subsets are distinct in magnitude of in vivo cytotoxic effector function, CD8+ T cell recall responses in vivo, molecular effector mechanisms which mediate cytotoxicity. Furthermore, these two pathways are differentially susceptible to conventional and experimental immunosuppressive agents. Dr. Bumgardner’s laboratory was the first to report the efficacy of a novel immunosuppressive strategy that successfully suppresses this immunoresistant (CD4-independent) CD8+ T cell mediated immune pathway and promotes long-term allograft survival. Very little is known regarding how CD8+ T cells cause immune damage of allografts and in vivo effector functions of alloreactive CD8+ T cells is a specific focus for investigation. Dr. Bumgardner’s lab is also investigating CD4-dependent humoral immune pathways of allograft damage. Her lab is the first to show that alloantibodies also mediate immune damage of transplanted hepatocytes by a macrophage-dependent, complement-independent, NK-independent cytotoxic effector mechanism. Studies are ongoing to investigate novel mechanisms governing the regulation of posttransplant alloantibody production in an animal model and to investigate translational aspects of these studies in humans. These and other projects have been funded by external sponsors, such as the American Diabetes Association, the Roche Organ Transplant Research Foundation, the American Society of Transplant Surgeons, the American Society of Transplantation and the National Institutes of Health.

Active Research Grants:
Nori US. A randomized, open-label, multicenter, parallel-group study of Belatacept-based Corticosteroid - free regimens in renal transplant. Bristol-Myers Squibb Co. June 2007 – December 2013, $59, 124

Nori US. A randomized, open-label, multicenter, parallel-group study of Belatacept-based Corticosteroid - free regimens in renal transplant. Bristol-Myers Squibb Co. June 2007 – December 2013, $22,108

Nori US. A randomized, open-label, multicenter, parallel-group study of Belatacept-based Corticosteroid - free regimens in renal transplant. Bristol-Myers Squibb Co. June 2007 – December 2013, $10,519

Moffatt-Bruce SD, Hadley GA, Sen CK. The role of T cells and macrophages in cardiac transplant rejection. National Heart, Lung, and Blood Inst. August 2010 – June 2015, $5,994

Rajab A, Ferguson RM, Henry ML, Pelletier RP. Rapid four day steroid withdrawal with thymoglobulin induction and maintenance immunosuppression with sirolimus and mycophenolate in primary cadaveric renal transplantation. December 2005 – January 2013, $32,859