Prolongation of composite tissue allograft survival by immature recipient dendritic cells pulsed with donor antigen and transient low-dose immunosuppression.
BACKGROUND
Composite tissue allograft transplantation is limited by risks of long-term immunosuppression. The authors investigated whether short-term immunosuppression combined with recipient immature dendritic cells pulsed with donor antigens promotes composite tissue allograft survival.


METHODS
Orthotopic hind-limb transplants were performed (day 0) from Wistar-Furth (RT1) to Lewis (RT1(u)) rats. Recipient dendritic cells were propagated from bone marrow with granulocyte-macrophage colony-stimulating factor (bone marrow-derived dendritic cells) and pulsed with or without donor splenic cell lysate. Recipients were as follows: group I, control; group II, cyclosporine (10 mg/kg/day, days 0 through 6, intraperitoneally); group III, antilymphocyte serum plus cyclosporine (days -4 and +1, intraperitoneally); and groups IV and V, cyclosporine plus antilymphocyte serum, combined with 7 x 10(6) untreated or donor cell lysate-pulsed bone marrow-derived dendritic cells (days +7 and +14, intravenously), respectively. Epidermolysis/desquamation of donor skin defined rejection. Mixed leukocyte reaction determined recipient T-cell reactivity to donor. Tissue samples were obtained at 3 weeks and on the day of rejection. Groups comprised six or seven rats.


RESULTS
Donor alloantigen-pulsed bone marrow-derived dendritic cells (group V) significantly prolonged median composite tissue allograft survival time (32.0 days) compared with groups II (18.0 days, p = 0.0012), III (22.5 days, p = 0.0043), and IV (26.5 days, p = 0.0043). Splenic T cells in group V exhibited hyporesponsiveness to donor alloantigen in mixed leukocyte reaction. Interestingly, the graft muscle component in the bone marrow-derived dendritic cell-treated group (group V) showed significant reduction in mononuclear cell infiltration relative to group II (p = 0.0317).


CONCLUSIONS
Donor alloantigen-pulsed recipient bone marrow-derived dendritic cells combined with transient T-cell-directed immunosuppression significantly prolonged composite tissue allograft survival across a full major histocompatibility complex barrier. This may represent the basis for a novel, clinically applicable strategy to promote composite tissue allograft survival with reduced systemic immunosuppression.
Sacks
Justin M
JM
Pittsburgh, Pa. From the Departments of Surgery and Immunology and the Division of Plastic and Reconstructive Surgery, Thomas E. Starzl Transplantation Institute, University of Pittsburgh, and the Department of Plastic and Reconstructive Surgery, Chang Gung Memorial Hospital.
Kuo
Yur-Ren
YR
Taieb
Aurele
A
Breitinger
Jeremy
J
Nguyen
Vu T
VT
Thomson
Angus W
AW
Feili-Hariri
Maryam
M
Lee
W P Andrew
WPA
D000818:Animals; D000941:Antigens / Q000276:immunology; D000961:Antilymphocyte Serum / Q000494:pharmacology; D016572:Cyclosporine / Q000494:pharmacology; D003713:Dendritic Cells / Q000276:immunology*; D004195:Disease Models, Animal; D006085:Graft Survival / Q000187:drug effects* / Q000276:immunology*; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D008297:Male; D051381:Rats; D011917:Rats, Inbred Lew; D011920:Rats, Inbred WF; D013154:Spleen / Q000166:cytology; D016378:Tissue Transplantation / Q000502:physiology; D014184:Transplantation, Homologous / Q000276:immunology
D000941:Antigens; D000961:Antilymphocyte Serum; D007166:Immunosuppressive Agents; D016572:Cyclosporine