Advances in immunosuppressive therapy have markedly improved allograft survival, but the treatment is still associated with significant morbidity. Truly long term success is likely to depend on the induction of donor-specific unresponsiveness (tolerance) towards allogenic tissue. One strategy for the induction of transplantation tolerance is now being tested in a preclinical primate model, and entails perioperative treatment with cytoablative therapy in the form of anti-thymocyte antibodies or anti-CD3 immunotoxin followed by administration of donor bone marrow. Although it has been established that there is functional elimination of anti-graft T-cell reactivity, little is known concerning the molecular and cellular basis of the interactions between donor bone marrow cells and graft specific t-cells. One functional model is based on the veto hypothesis, which postulates that a subpopulation of donor bone marrow cells (veto cells) are capable of deleting or inactivating the graft specific cytolytic T cells that mediate graft rejection. This proposal investigates the concept that bone marrow induced tolerance is initiated and maintained when CD8+ donor bone marrow cells become resident in the transplant recipient and actively delete donor-reactive T cells. This deletion occurs by induction of apoptosis via ligation of the Fas receptor on the donor-reactive t cells by the Fas ligand molecule expressed on the donor bone marrow cells. By in vitro modification of bone marrow cells using recombinant viruses, through the use of transgenic mice and mice with targeted mutations, and through functional studies of veto cell activity in vitro they will specifically address the question of involvement of the CD8 and Fas/Fas-ligand molecules in the functional inactivation of donor specific T cells.
The specific aims of this proposal are 1) To determine the role of the Fas/Fas ligand pathway of apoptosis induction in bone marrow induced transplantation tolerance. 2) Investigate the role of the CD8 molecule in the induction of tolerance. 3) Determine the functional relationshop of CD8 and Fas-ligand on donor bone marrow cells and examine the functional effects on donor reactive T cells following exposure to donor bone marrow cells. 4) Determine the fate of graft reactive T cells in vivo following infusion of donor bone marrow cells. The information generated will provide information regarding the specific cellular and subcellular events that are critical to the induction and maintenance of tolerance in this system.
|George, James F; Lu, Ailing; Thomas, Judith M et al. (2003) Allogeneic bone marrow inhibits T-cell activation and clonal expansion in vitro. Transplantation 76:237-43|
|Goldstein, D R; Thomas, J M; Kirklin, J K et al. (2001) An essential role for natural killer cells in augmentation of allograft survival mediated by donor spleen cells. Transplantation 72:954-6|
|Goldstein, D R; Chang, T; Sweeney, S D et al. (2000) Enhanced allograft survival induced by posttransplant donor spleen cell infusion occurs via a mechanism that is distinct from the mechanism of enhancement by donor bone marrow. Transplantation 69:1020-2|
|Goldstein, D R; Chang, T; Sweeney, S D et al. (2000) A differential requirement for CD8+ donor cells in the augmentation of allograft survival by posttransplantation administration of donor spleen cells and donor bone marrow cells. Transplantation 70:1068-73|
|George, J F; Goldstein, D R; Thomas, J M (1999) Donor bone marrow and transplantation tolerance: historical perspectives, molecular mechanisms and future directions (review). Int J Mol Med 4:475-82|