Induction of hematopoietic cellular chimerism through bone marrow transplantation can lead to life-long transplantation tolerance without the need for chronic immunosuppression. However, bone marrow transplantation across major histocompatibility (MHC) barriers is severely limited by problems associated with the severity of the host preparative regimen required to achieve engraftment, the potential for lethal graft-versus-host disease (GVHD), and a high rate of engraftment failure. These problems could potentially be avoided by using a gene therapy approach to introduce allogeneic MHC genes into autologous bone marrow resulting in a state of molecular rather than cellular chimerism. In the last funding period, we examined whether such a gene therapy based approach could be used to induce tolerance to an allogeneic major histocompatibility (MHC) class I antigen. Reconstitution of lethally irradiated B10.AKM mice (H-2Kk, Ik, Dq) with syngeneic bone marrow infected with retroviruses carrying the allogeneic MHC class I gene H-2Kb, resulted in life-long expression of Kb on the surface of bone marrow cells, and specific tolerance to Kb. Mice reconstituted with H-2Kb transduced bone marrow accepted K b disparate skin allografts long-term without the need for any additional immunosuppression. Thus, genetic engineering of bone marrow using retroviral transduction to establish molecular chimerism can be used to induce long-term stable tolerance to transplantation antigens, effectively re-shaping the immunological repertoire.
The specific aims of this proposal are: 1) To determine the mechanism by which CD4 T cell tolerance induced by gene therapy is maintained in molecular chimeras; 2) Develop clinically relevant non-myeloablative protocols to induce tolerance by genetic engineering of bone marrow; and 3) Test the hypothesis that induction of molecular chimerism can be used to induce tolerance to MHC class I and class II disparate grafts and prevent acute as well as chronic allograft rejection. These studies should expand the use of gene therapy to induce immunological tolerance, provide practical information important for the field of transplantation on mechanisms of tolerance, and may also advance our understanding of self-nonself discrimination with respect to MHC antigens. Ultimately, these studied may provide a novel means of inducing acceptance of allogeneic organ transplants without the need for life-long immunosuppression.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Special Emphasis Panel (ZRG1-SAT (90))
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Koh, Crystal Y
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Brigham and Women's Hospital
United States
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Jindra, P T; Tripathi, S; Tian, C et al. (2013) Tolerance to MHC class II disparate allografts through genetic modification of bone marrow. Gene Ther 20:478-86
Zhao, X; Boenisch, O; Yeung, M et al. (2012) Critical role of proinflammatory cytokine IL-6 in allograft rejection and tolerance. Am J Transplant 12:90-101
Tian, Chaorui; Yuan, Xueli; Jindra, Peter T et al. (2010) Induction of transplantation tolerance to fully mismatched cardiac allografts by T cell mediated delivery of alloantigen. Clin Immunol 136:174-87
Tian, Chaorui; Yuan, Xueli; Bagley, Jessamyn et al. (2008) Induction of transplantation tolerance by combining non-myeloablative conditioning with delivery of alloantigen by T cells. Clin Immunol 127:130-7
Tian, Chaorui; Ansari, Mohammed Javeed I; Paez-Cortez, Jesus et al. (2007) Induction of robust diabetes resistance and prevention of recurrent type 1 diabetes following islet transplantation by gene therapy. J Immunol 179:6762-9
Tian, C; Bagley, J; Iacomini, J (2007) Homeostatic expansion permits T cells to re-enter the thymus and deliver antigen in a tolerogenic fashion. Am J Transplant 7:1934-41
Bagley, Jessamyn; Tian, Chaorui; Iacomini, John (2007) New approaches to the prevention of organ allograft rejection and tolerance induction. Transplantation 84:S38-41
Tian, C; Bagley, J; Forman, D et al. (2006) Inhibition of CD26 peptidase activity significantly improves engraftment of retrovirally transduced hematopoietic progenitors. Gene Ther 13:652-8
Tian, C; Bagley, J; Iacomini, J (2006) Persistence of antigen is required to maintain transplantation tolerance induced by genetic modification of bone marrow stem cells. Am J Transplant 6:2202-7
Forman, Daron; Kang, Eun-Suk; Tian, Chaorui et al. (2006) Induction of alloreactive CD4 T cell tolerance in molecular chimeras: a possible role for regulatory T cells. J Immunol 176:3410-6

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