TY - JOUR
T1 - Rapamycin-conditioned, alloantigen-pulsed dendritic cells promote indefinite survival of vascularized skin allografts in association with T regulatory cell expansion
AU - Horibe, Elaine K.
AU - Sacks, Justin
AU - Unadkat, Jignesh
AU - Raimondi, Giorgio
AU - Wang, Zhiliang
AU - Ikeguchi, Ryosuke
AU - Marsteller, Douglas
AU - Ferreira, Lydia M.
AU - Thomson, Angus W.
AU - Lee, W. P.Andrew
AU - Feili-Hariri, Maryam
N1 - Funding Information:
The authors thank the University of Pittsburgh Center for Biological Imaging for valuable assistance with immunofluorescence images. This study was supported in part by the American Society for Surgery of the Hand (MF-H), the Plastic Surgery Educational Foundation (EKH), a research training fellowship from the Transplantation Society (GR), and by National Institutes of Health grants AI67541 and AI60994 (AWT). EKH was in a receipt of a Research Fellowship from the Brazilian Ministry of Education Foundation.
PY - 2008/2
Y1 - 2008/2
N2 - Clinically-applicable protocols that promote tolerance to vascularized skin grafts may contribute to more widespread use of composite tissue transplantation. We compared the properties of alloantigen (Ag)-pulsed, rapamycin (Rapa)-conditioned and control bone marrow-derived host myeloid dendritic cells (DCs) and their potential, together with transient immunosuppression (anti-lymphocyte serum + cyclosporine), to promote long-term, vascularized skin graft survival in Lewis rats across a full MHC barrier. Both types of DCs expressed low levels of CD86, but Rapa DC expressed lower levels of MHC II and CD40 and were less stimulatory in MLR. While both Rapa and control DCs produced low levels of IL-12p70 and moderate levels of IL-6 and IL-10 following TLR ligation, Rapa DC secreted significantly lower levels of IL-6 and IL-10 in response to LPS. Donor Ag-pulsed Rapa DC, but not control DC, induced long-term skin graft survival (median survival time > 133 days) when administered 7 and 14 days post-transplant. Circulating T cells in hosts with long-surviving grafts were hyporesponsive to donor alloAg stimulation, but proliferated in response to third-party stimulation and produced IFN-γ and IL-10. When recipients of long-surviving grafts were challenged with skin grafts, donor but not third-party grafts were prolonged, suggesting underlying regulatory mechanisms. Both flow cytometry and immunohistochemical analysis revealed that donor Ag-pulsed Rapa DC infusion expanded CD4+ Foxp3+ Treg in recipients' spleens, graft-associated lymph nodes and the graft. These data demonstrate for the first time that pharmacologically-modified, donor Ag-pulsed host DC administered post-transplant can promote indefinite vascularized skin graft survival, associated with Treg expansion.
AB - Clinically-applicable protocols that promote tolerance to vascularized skin grafts may contribute to more widespread use of composite tissue transplantation. We compared the properties of alloantigen (Ag)-pulsed, rapamycin (Rapa)-conditioned and control bone marrow-derived host myeloid dendritic cells (DCs) and their potential, together with transient immunosuppression (anti-lymphocyte serum + cyclosporine), to promote long-term, vascularized skin graft survival in Lewis rats across a full MHC barrier. Both types of DCs expressed low levels of CD86, but Rapa DC expressed lower levels of MHC II and CD40 and were less stimulatory in MLR. While both Rapa and control DCs produced low levels of IL-12p70 and moderate levels of IL-6 and IL-10 following TLR ligation, Rapa DC secreted significantly lower levels of IL-6 and IL-10 in response to LPS. Donor Ag-pulsed Rapa DC, but not control DC, induced long-term skin graft survival (median survival time > 133 days) when administered 7 and 14 days post-transplant. Circulating T cells in hosts with long-surviving grafts were hyporesponsive to donor alloAg stimulation, but proliferated in response to third-party stimulation and produced IFN-γ and IL-10. When recipients of long-surviving grafts were challenged with skin grafts, donor but not third-party grafts were prolonged, suggesting underlying regulatory mechanisms. Both flow cytometry and immunohistochemical analysis revealed that donor Ag-pulsed Rapa DC infusion expanded CD4+ Foxp3+ Treg in recipients' spleens, graft-associated lymph nodes and the graft. These data demonstrate for the first time that pharmacologically-modified, donor Ag-pulsed host DC administered post-transplant can promote indefinite vascularized skin graft survival, associated with Treg expansion.
KW - Dendritic cells
KW - Rat
KW - Tolerance
KW - Treg
KW - Vascularized skin allograft
UR - http://www.scopus.com/inward/record.url?scp=37349068519&partnerID=8YFLogxK
U2 - 10.1016/j.trim.2007.10.007
DO - 10.1016/j.trim.2007.10.007
M3 - Article
C2 - 18158116
AN - SCOPUS:37349068519
SN - 0966-3274
VL - 18
SP - 307
EP - 318
JO - Transplant Immunology
JF - Transplant Immunology
IS - 4
ER -