Endogenous Dendritic Cells Mediate The Effects Of Intravenously Injected Therapeutic Immunosuppressive Dendritic Cells In Transplantation

Heart transplant is an effective therapy for end-state heart diseases. Althoughshort-term survival post transplant has been improved significantly during the pastdecades, long-term posttransplant survival remains to be low. Since obvious defectsexist in currently available immunosuppressants, long-term mortality and morbidityare associated with over-immunosuppression (infection, malignancy) or ineffectiveimmunosuppression (rejection, coronary allograft disease, late graft failure).Therefore, rejection, for which chronic immunosuppression has to be maintained, isthe most important hurdle to long-term posttransplant survival and also yet to besolved. Much investigation has been performed to develop donor-specificimmunosuppression or tolerance induction, in which dendritic cell (DC) is one of thetargets. During the past decade, numerous studies have unveiled mechanisms bywhich different subsets of DCs induce or maintain self-tolerance in vivo. TolerogenicDCs are immature, maturation-resistant or alternatively activated DCs that expresssurface MHC molecules, have a low ratio of co-stimulatory to inhibitory signals, andan impaired ability to synthesize T helper1-cell-driving cytokines. The prevailingidea regarding the mechanism(s) by which therapeutic immunosuppressive DCsrestrain alloimmunity is based on the concept that they interact directly withanti-donor T cells, inducing anergy, deletion and/or regulation. However, this idea hasnot been tested in vivo.Using prototypic maturation-resistant (MR) DCs in vitro-generated with VitaminD3, we demonstrate that once MR-DCs carrying donor-Ag are administered i.v., they decrease the direct and indirect pathway T cell responses and prolong heart allograftsurvival, but fail to directly regulate T cells in vivo when studied with transgenic Tcells. Rather, injected MR-DCs are short-lived and re-processed by recipient DCs forpresentation to indirect pathway CD4＋T cells, resulting in abortive activation anddeletion without detrimental effect on the number of indirect CD4＋FoxP3＋T cells,thus increasing the regulatory to effector T cell relative percentage. The effect on theanti-donor response was independent of the method used to generate therapeutic DCsor their viability, and in accordance with the idea that recipient Ag-presenting cellsmediate the effects of therapeutic DCs in transplantation, prolongation of allograftsurvival was achieved using donor apoptotic MR-DCs or those lacking surface MHCmolecules.In conclusion, therapeutic DCs function as antigen transporting cells rather thanAg-presenting cells to prolong allograft survival. In the current model, endogenousdendritic cells mediate the effects of intravenously injected therapeuticimmunosuppressive DCs in transplantation. Therefore, costs and benefits should beconsidered when DC-based therapy is used in the settings of immunosuppression intransplantation.