Why do we reject a graft? Role of indirect allorecognition in graft rejection

Taken together, these experimental observations in animals as well as humans have led to the formulation of a hypothesis linking MHC-allopeptide- primed T-cells and chronic rejection (Fig. 4). Small numbers of indirectly primed T-cells are present and targeted against a restricted repertoire of immunodominant peptides in the immediate post-transplant period. Concomitant with the possible decline in the importance of directly primed T-cells with time post engraftment [40, 57], the precursor frequency of indirectly primed T-cells continues to be low grade. In addition, naive CD4+ T-cells recognize new epitopes, by a yet unclear mechanisms, and are continuously becoming activated while immunosuppression is being reduced. Activated CD4± T-cells provide help and in turn activate the effector mechanism of allograft destruction, namely, monocytes/macrophages (DTH), shifting. Several strategies hold promise in that regard. In particular, strategies targeted at blocking CD28-B7 and/or CD40L-CD40 T-cell co-stimulatory activation have been shown to prevent development [59-64] and even interrupt progression [65] of chronic rejection in experimental animals. Interestingly, targeting T-cell co-stimulatory activation also might be effective in ameliorating injury mediated by alloantigen-independent mechanisms of graft dysfunction, such as ischemia/reperfusion injury [11, 12]. Obviously, the applicability of these rodent studies needs to be confirmed in large animals [66] before clinical trials in humans are begun.