Ex-vivo expanded DCs induce donor-specific central and peripheral tolerance and prolong the acceptance of donor skin allografts (169.12)

Abstract

Abstract The principal function of Dendritic cells (DCs) is to promote T cell activation and differentiation into effecter T cells by presenting foreign Ags and providing costimulatory signals. Also DCs are known to regulate immune responses by inducing both central and peripheral tolerance. DCs play a vital role in negative selection of developing thymocytes by deleting T cells with high-affinity for self-peptide-MHC complexes. In the periphery, DCs mediate peripheral tolerance by promoting regulatory T cell development, induction of T cell unresponsiveness, and deletion of activated T cells. We studied whether allogeneic DCs obtained from bone marrow cultured either with Flt3L (FLDC) or GM-CSF (GMDC) could induce allo-specific central and peripheral tolerance after i.v. injection; B cells were used as a control. The results showed that only FLDC reached the thymus after injection, and these cells induced both central and peripheral tolerance to donor MHC. For central tolerance, injection of FLDC induced antigen-specific negative selection of both CD8 and CD4 single-positive thymocytes. For peripheral tolerance, injection of FLDC induced donor-specific T cell unresponsiveness and prolonged survival of donor-derived skin grafts. Tolerance induction by adoptive transfer of Flt3L-induced DC could be a useful approach for promoting graft acceptance after organ transplantation.