The existence of two sets of dendritic cells in transplantation (of donor and recipient origin) poses unique problems in alloimmunity and tolerance. Donor DCs are potent stimulators of the direct pathway, in which recipient T cells respond to peptides presented on donor MHC products or to the donor MHC molecules themselves. Reduced DC function in the direct pathway is used to explain the acceptance of certain allografts that have been depleted of passenger leukocytes. Reciprocally, purified donor DCs powerfully stimulate the rejection of these grafts as well as the mixed leukocyte reaction by purified allogeneic T cells in culture. Donor DCs also can act as specialized antigen transport vehicles in cross-priming for the indirect pathway. Here, recipient DCs process MHC molecules from the donor. The indirect pathway of rejection is actually the rule for passenger leukocyte-depleted grafts. Furthermore, the indirect pathway seems to be the dominant alloresponse detected in long-term graft recipients, both in experimental models and clinical transplantation, particularly in those with chronic rejection. The stimulatory function of DCs in both direct and indirect pathways is regulated by their maturation in response to inflammatory stimuli, especially those delivered via IL-1, TNF, and Toll receptor families. Since the normal function of DCs is to generate immunity against invading pathogens, the indirect response to peptides continually derived from the allogeneic MHC molecules in a tissue allograft (a surgically introduced "pathogen" because of the associated inflammation and necrosis) may be more difficult to silence. However, in addition to their allostimulatory role, immature or in vitro-manipulated DCs also have the potential to downregulate direct and indirect antidonor responses through a variety of mechanisms. Intriguing new evidence shows that immature DCs can actively induce regulatory T cells. Given the probable role of the indirect pathway in driving chronic rejection, the induction of T cell tolerance (deletion, anergy, and regulation), especially in those T cells with indirect antidonor allospecificity, by the injection of immature DCs pretransplant, could serve as a critical therapeutic strategy.
