title: Rapamycin-treated, alloantigen-pulsed host dendritic cells induce ag-specific T cell regulation and prolong graft survival.
abstract: Tolerogenic properties of dendritic cells (DC), particularly those in the immature state, and their therapeutic potential are increasingly being recognized. Among several distinct approaches to generate stably immature DC, pharmacologic manipulation stands out as a promising and clinically applicable option. We have shown recently that the immunophilin ligand rapamycin (Rapa) can inhibit DC maturation and their effector functions. Here, we examined the impact of Rapa exposure on subsequent alloantigen (Ag) presentation by myeloid DC via the indirect pathway. Rapa-treated, allogeneic lysate-pulsed host DC (Rapa-DC) were inferior stimulators of syngeneic T cells, compared to lysate-pulsed control DC. Rapa exposure did not block alloAg uptake by DC nor impair their in vivo homing to splenic T cell areas after adoptive transfer. T cells primed by Rapa-treated, alloAg-pulsed DC showed decreased capacity to produce IL-2 and IFNgamma, and were hyporesponsive to subsequent challenge via both the direct and indirect pathways, in an Ag-specific manner. When infused 1 week before transplantation, these Rapa-DC significantly prolonged alloAg-specific heart graft survival. This effect was reversed by systemic IL-2 administration but enhanced by either repeated infusion of the cells or a short post-transplant course of FK506. These therapeutic effects, achieved by targeting both major pathways of allorecognition, provide the basis for a clinically applicable strategy to suppress graft rejection.
authors.affiliation: Department of Surgery, Thomas E. Starzl Transplantation Institute, University of Pittsburgh, PA, USA.
authors.forename: Timuçin
authors.initials: T
authors.lastname: Taner
authors.forename: Holger
authors.initials: H
authors.lastname: Hackstein
authors.forename: Zhiliang
authors.initials: Z
authors.lastname: Wang
authors.forename: Adrian E
authors.initials: AE
authors.lastname: Morelli
authors.forename: Angus W
authors.initials: AW
authors.lastname: Thomson
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D002465:Cell Movement / Q000276:immunology; D003713:Dendritic Cells / Q000187:drug effects* / Q000276:immunology; D006085:Graft Survival / Q000276:immunology*; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007371:Interferon-gamma / Q000378:metabolism; D007376:Interleukin-2 / Q000378:metabolism; D007519:Isoantigens / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D020123:Sirolimus / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism
chemical_list: D007166:Immunosuppressive Agents; D007376:Interleukin-2; D007519:Isoantigens; D007371:Interferon-gamma; D020123:Sirolimus