Dendritic cells, tolerance and therapy of organ allograft rejection

Donor dendritic cells (DCs) and those of host origin play key roles in the instigation and maintenance of immune responses to organ allografts. In the normal steady state, however, DCs are important for the maintenance of central and peripheral tolerance. Moreover, the presence of those cells in donor hematopoietic cell infusions may facilitate the induction of transplant tolerance. Accrual of information regarding DC tolerogenicity has driven the assessment of DC-based therapy of allograft rejection. Pioneering work demonstrating increased allograft survival after pretransplant infusion of immature donor-derived DC has prompted the evaluation of several approaches to the generation of DCs with tolerogenic/regulatory properties. These include: identification of specific culture conditions for propagation of homogenous populations of immature DCs; pharmacological manipulation of DCs to stabilize their immature/tolerogenic phenotype; and genetic modification of DCs to impair their stimulating ability/enhance their tolerogenicity. These approaches have rendered DCs capable of markedly prolonging experimental allograft (including kidney transplant) survival and promoting donor-specific tolerance. Recently identified molecular signaling pathways that play key roles in the outcome of DC-T cell interaction are likely to become novel targets for manipulation of allograft immunity and for the promotion of transplant tolerance.