TY - JOUR
T1 - Rapamycin-treated, alloantigen-pulsed host dendritic cells induce Ag-specific T cell regulation and prolong graft survival
AU - Taner, Timuçin
AU - Hackstein, Holger
AU - Wang, Zhiliang
AU - Morelli, Adrian E.
AU - Thomson, Angus W.
PY - 2005/2
Y1 - 2005/2
N2 - 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 IFNγ, 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.
AB - 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 IFNγ, 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.
KW - Antigen presentation/processing
KW - Dendritic cell
KW - Tolerance
KW - Transplantation
UR - http://www.scopus.com/inward/record.url?scp=13144256708&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=13144256708&partnerID=8YFLogxK
U2 - 10.1046/j.1600-6143.2004.00673.x
DO - 10.1046/j.1600-6143.2004.00673.x
M3 - Article
C2 - 15643982
AN - SCOPUS:13144256708
SN - 1600-6135
VL - 5
SP - 228
EP - 236
JO - American Journal of Transplantation
JF - American Journal of Transplantation
IS - 2
ER -