Induction of lymphohematopoietic chimerism through bone marrow transplantation (BMT) can lead to life-long transplantation tolerance without the need for chronic immunosuppression. However, BMT across major histocompatibility (MHC) barriers is severely limited by problems associated with the severity of the host preparative regimen required, the potential for lethal graft-versus-host disease (GVHD), and engraftment failure. These problems could potentially be avoided by using a gene therapy approach to introduce allogeneic MHC genes into autologous bone marrow rather than transferring immunocompetent cells into the host. Using retroviral gene therapy, the allogeneic MHC class I gene H-2Kb (Kb) has been introduced into syngeneic bone marrow. Reconstitution of lethally irradiated syngeneic mice with bone marrow transduced with the Kb gene has been found to produce the specific prolongation of Kb bearing skin allograft survival. The major goals of this proposal are to examine the mechanism(s) by which expression of the transduced allogeneic MHC gene in BM derived cells lead to prolonged survival of Kb disparate skin grafts, and to establish conditions permitting long-term expression of the transduced gene in BM derived cells for the purpose of inducing life-long allograft acceptance.
The specific aims are to: 1) Establish conditions permitting long-term expression of the retrovirally transduced H-2Kb gene in bone marrow derived cells; 2) Determine the mechanism by which expression of the transduced MHC class I gene product affects reactivity of anti-Kb CD8 T cells. 3) Determine the mechanism by which expression of retrovirally transduced Kb in bone marrow derived cells affects the ability of CD4 T cells to respond Kb disparate targets; and, 4) Evaluate the ability of Kb expressing cells of various lineages to induce specific prolongation of Kb disparate skin graft survival. These studies should provide practical information important for the field of transplantation on the mechanism of tolerance induced by gene therapy, and should also provide theoretical insights which may advance our understanding of self-nonself discrimination with respect to MHC antigens.
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