Bone marrow transplantation (BMT) is a widely employed therapy for the treatment of a variety of diseases. However, the T cell depletion (TCD) of the donor graft that is required to prevent graft-vs.-host disease (GvHD) also decreases immunity to microbial pathogens, leaving the BMT recipient susceptible to opportunistic infections. The mortality rates from opportunistic infection in the post-TCD BMT setting can approach 50% resulting in considerable morbidity and mortality in BMT patients. The ultimate goal of immunotherapeutic approaches to the above problem is the specific elimination of alloreactive T cells that cause GvHD but not T cells involved in immunity to microbial pathogens. Veto activity is a well-described mechanism for selectively removing alloreactive T cells. The central hypothesis of this grant application is that ex-vivo expanded allospecific veto cells of recipient origin can be utilized to specifically delete donor T cells responsible for GvHD without eliminating T cells involved in immunity to microbial pathoqens. We propose to test this hypothesis by applying veto cells to a murine model of MHC mismatched BMT and post-transplant infection with murine cytomegalovirus (MCMV).
Two specific aims are proposed. (1) Test the ability of veto cells to prevent GvHD and (2) Test the effect of veto cells on MCMV immunity. The proposed studies will provide a well-controlled experimental setting to test our hypothesis, refine this approach to allo-tolerization, and lay the conceptual and technical groundwork for the application of this approach to human BMT. This approach may result in a significant decrease in morbidity and mortality in BMT procedures that are being performed with increasing frequency for a variety of diseases and has particular relevance to BMT strategies that entail significant MHC mismatch such as haplo-identical transplants. In addition, this strategy has relevancy to other issues of allo-tolerization including solid organ transplantation. In keeping with the stated purpose of this RFA, these studies represent the """"""""development and application of cell engineering methods to predictably induce tolerance..."""""""" ? ?
| Anderson, Kimberly M; Zimring, James C (2006) Rapamycin prolongs susceptibility of responding T cells to tolerance induction by CD8+ veto cells. Transplantation 81:88-94 |
