Successful allogeneic bone marrow transplantation (BMT) is contingent upon the establishment of durable donor engraftment, the retention of the graft-versus-leukemia effect and the amelioration of toxicity from graft-versus-host disease (GVHD). Donor T cells play a pivotal role in facilitating allo engraftment and mediating the GVL effect but also initiate GVHD, which is the major complication of allogeneic BMT. Current GVHD prevention strategies such as ex vivo T cell depletion of the donor marrow graft have been effective at preventing GVHD but have had the unintended effects of increasing graft rejection and disease relapse as well as impairing immune reconstitution. As an alternative strategy, the applicant has examined an approach that allows for the selective in vivo manipulation of donor T cells at defined time points in the host. He has developed a murine model using donor transgenic mice whose T cells have been engineered to express the thymidine kinase (TK) gene. Use of these mice as donors in allogeneic marrow transplant experiments permits the selective elimination of T cells at defined intervals by administration of the antiviral agent ganciclovir. Consequently, the role of donor T cells in preventing relapse, facilitating engraftment, and causing GVHD can be assessed in a dynamic fashion. He hypothesizes that GVHD can be successfully modulated using gene modified donor T cells such that the beneficial GVL and graft promoting effects associated with or independent of GVHD are retained while collateral GVH-related host tissue damage is mitigated.
The specific aims of this application are: 1) to determine whether the selective elimination of mature donor TK+ T cells post-transplant is able to mitigate GVHD without compromising GVL reactivity, 2) to define how the activation status of the donor T cell prior to transplantation affects GVL reactivity, 3) to determine how the elimination of host-reactive donor T cells affects the residual immune response to third party and viral infection, and 4) to determine how the elimination of TK+ transgenic donor T cells post-transplant affects GVH/GVL reactivity in suboptimally conditionally recipients. The overall goal of this project is to selectively modulate T-cell function and survival in vivo in order to augment the therapeutic index of allogeneic BMT.
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