Graft acceptance following transplantation has improved over the past twenty years with T cells directed immunosuppressive treatments. Despite the improvement in short-term results, the half-life of transplants has remained the same as the result of chronic rejection, which represents the main cause of long-term graft failure. MHC-directed graft specific antibodies (alloantibodies) significantly contribute to graft loss due to acute humoral rejection as well as chronic rejection. Another mechanism for both graft rejection is the production of graft specific antibodies (alloantibodies), thus leading to graft destruction. We and others have shown that CD8+ T cell depletion significantly enhances alloantibody production posttransplant. Our preliminary data demonstrate that CD8+ T cells actively suppress production of alloantibody posttransplant since adoptive transfer of CD8+ T cells into CD8-deficient recipients prior to transplant suppresses alloantibody production posttransplant. Therefore, the overall goal of this project is to determine the precise mechanism(s) by which CD8+ T cells regulate immune responses associated with antibody production. This will be addressed by investigating two aims:
Aim 1) Determine whether CD8+ T cells regulate alloantibody production by altering the Th1/Th2 cytokine balance, Aim 2) Determine whether alloreactive CD8+ T cells regulate alloantibody production by the destruction of alloreactive B cells. These potential mechanisms will be addressed utilizing a mouse model of transplantation. Briefly, mice that are deficient in CD8+ T cells (high alloantibody producers) will be compared to their wild type counterparts following transplantation. In addition, CD8+ T cells [wild type or lacking various effector molecules (i.e., FasL, perforin)], will be adoptively transferred into CD8-deficient mice to evaluate the impact of CD8+ T cells on IFN-gamma and IL-4 cytokine levels (locally and systemically) and CD8-mediated B cell killing. Concurrently, the importance of FasL and performexpression by CD8+ T cells upon cytokine levels, B cell killing, and alloantibody production posttransplant will be examined.
Although current immunosuppressive agents protect transplant patients from early rejection, delayed rejection remains an important problem. Alloantibody contribute to early and late graft loss due to acute and chronic rejection respectively. Our preliminary work shows that CD8+ T cells suppress the production of alloantibodies. Therefore, it is imperative that the mechanism of CD8+ T cell-mediated alloantibody regulation is revealed;this research may lead to innovative immunosuppressive strategies which prevents alloantibody production and improves longterm graft survival.
