The role of CD40-CD40 ligand interactions in transplantation

The major obstacle still facing long-term graft acceptance is the strong T cell mediated immune response directed at the graft. Currently administered immunosuppressive regimens cause severe side effects most notably systemic immunosuppression. Therefore, an ideal immunosuppressive therapy would be one that's administered during the inductive phase of T cell activation and target alloreactive T cells. Blockade of the CD40-CD40L T cell costimulatory pathway is a promising target for inducing transplantation tolerance. Thus, the focus of this dissertation was to further elucidate the role of CD40-CD40L interactions in transplantation. This question was addressed through (1) The use of CD40−/− allograft recipients and donors and (2) Treatment of WT cardiac allograft recipients with anti-CD40L mAb therapy.; CD40-CD4OL interactions were not requisite for allograft rejection, in that CD40−/− BALB/c and CD40−/− C57BL/6 recipients rejected CD40−/− allografts. However, further analysis revealed that the ability of CD40−/− recipients to reject WT allografts was strain specific. Immunologic assessment revealed that Thl priming was markedly inhibited in CD40−/− C57BL/6 recipients that rejected their grafts compared to WT C57BIJ6 recipients.Anti-CD40L blockade prolonged allograft survival in CD40−/−; C57BL/6 recipients of CD40−/− allografts, but not CD40−/−-BALB/c recipients. Finally, CD40-CD40L independent CD8+ T cells appear to be required for rejection mediated in CD40−/− recipients.; Inductive treatment of WT cardiac allograft recipients with anti-CD40L was effective at prolonging allograft survival, which is not associated with a deletion of donor-reactive IL-2 producing helper, cytolytic or IFNγ producing T cells. These mice retained the ability to reject donor strain skin allografts, but failed to reject the original cardiac allograft or a second donor strain cardiac allograft. Further characterization of cells obtained from mice bearing long-term cardiac allografts demonstrated that longterm graft acceptance was not associated with decreased immunogenicity of the original cardiac allograft A series of adoptive transfer experiments utilizing mice bearing longterm cardiac allografts suggested the presence of a putative regulatory cell population following inductive anti-CD40L blockade. In vitro and in vivo analysis indicated that anti-CD40L therapy induced IL-10 producing regulatory cells that controlled III responsiveness. However, anti-IL-10 treatment Med to ablate long-term graft acceptance induced by anti-CD40L therapy. Collectively these data suggest the presence of an IL-10 producing regulatory cell population that is involved in maintaining long-term graft acceptance following inductive anti-CD40L therapy.