Long-term survival of limb allografts induced by pharmacologically conditioned, donor alloantigen-pulsed dendritic cells without maintenance immunosuppression.
BACKGROUND
We showed recently that limb allograft survival could be enhanced by administration of alloantigen (Ag)-pulsed immature dendritic cells (DC) after transplantation. Since indefinite graft survival was not achieved, we have further modified the DC by pharmacologic (rapamycin; Rapa) conditioning and ascertained their influence on graft survival, without continued immunosuppressive therapy.


METHODS
We compared the ability of donor Ag-pulsed, Rapa-conditioned rat myeloid DC (Rapa DC) and control DC (CTR DC) to inhibit alloreactive T-cell responses after limb transplantation in antilymphocyte serum (ALS)-treated recipients given a short postoperative course of cyclosporine (CsA).


RESULTS
Both DC populations expressed similar levels of major histocompatibility complex (MHC) II, CD40 and CD54, but Rapa DC expressed lower CD86. After toll-like receptor activation, both populations produced minimal interleukin (IL)-12p70, but Rapa DC secreted lower levels of IL-6 and IL-10. The capacity of DCs to stimulate T-cell proliferation in mixed leukocyte reactions was very low. Pulsing of the DC with donor Ag did not alter their phenotype or function. Interestingly, posttransplant administration of donor Ag-pulsed Rapa DC to rats given perioperative ALS and 21 days CsA significantly delayed graft rejection and promoted long-term (>125 days) graft survival. AlloAg-pulsed Rapa DC induced T-cell hyporesponsiveness and promoted the generation of IL-10-secreting CD4 T cells upon ex vivo challenge.


CONCLUSIONS
Infusion of donor Ag-pulsed, Rapa-conditioned DC after composite tissue transplantation can prevent rejection of the grafts, including skin, across a full MHC mismatch and in the absence of continued immunosuppressive therapy.
Ikeguchi
Ryosuke
R
Department of Surgery, Division of Plastic and Reconstructive Surgery, University of Pittsburgh, Pittsburgh, PA 15261, USA.
Sacks
Justin M
JM
Unadkat
Jignesh V
JV
Solari
Mario
M
Horibe
Elaine K
EK
Thomson
Angus W
AW
Lee
Andrew W P
AW
Feili-Hariri
Maryam
M
D000818:Animals; D001854:Bone Marrow Cells / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology* / Q000637:transplantation*; D006085:Graft Survival; D006614:Hindlimb / Q000637:transplantation*; D007165:Immunosuppression Therapy; D007166:Immunosuppressive Agents / Q000494:pharmacology; D007371:Interferon-gamma / Q000378:metabolism; D007519:Isoantigens / Q000494:pharmacology*; D008297:Male; D051381:Rats; D011917:Rats, Inbred Lew; D011920:Rats, Inbred WF; D017207:Rats, Sprague-Dawley; D020123:Sirolimus / Q000494:pharmacology; D018183:Transplantation Chimera; D014184:Transplantation, Homologous / Q000502:physiology*
D007166:Immunosuppressive Agents; D007519:Isoantigens; D007371:Interferon-gamma; D020123:Sirolimus