Immunological evaluation of combination therapy with tacrolimus and sirolimus on long-term allograft survival in nonhuman primates.
We reported that a 60-day course of combination therapy with tacrolimus and sirolimus induced long-term survival of renal allograft after withdrawal of immunosuppressants in Vervet monkeys. In the present study, the mechanism of drug-induced allograft survival was evaluated via Th1/Th2 cytokines, apoptosis and MLC activity in primates.


METHODS
Cytokines were evaluated by ELISA. MLR and CTL assays were performed by incorporation of 72 hours (3)H-TdR and 4 hours (51)Cr release assay.


RESULTS
A 60-day course of tacrolimus with sirolimus resulted in long-term survival of kidney allografts. (67% > 100 days) without intermittent acute rejection. Low sensitivity to MLR was seen in long-term renal allograft survival among monkeys treated with tacrolimus and sirolimus. Increased levels of CD3(+)CD8(+), CD3(+)/CD56(+) NKT cells and CD86(+)CD8(-)CD11(+) dendritic cells were observed. A population of high expression of CD4(+)FasL(+) was detected. In addition, the concentrations of IL-2 and IFN-gamma from long-term allograft surviving monkeys was not significantly increased, rather a late phase dominance of Th2, IL-4, IL-10, and TGF-beta was found correlated with long-term survival of recipients. In conclusion, the mechanism of tacrolimus and sirolimus induced long-term allograft survival in primates relates to up-regulated FasL expression, NKT cells and dendritic cells, with downregulation of MLR sensitivity. It is also associated with late-dominant expression of Th2 cytokines.
Ma
A
A
Laboratory of Experimental Surgery, Research Center of CHUM, Notre-Dame Hospital, University of Montreal, Montreal, Quebec, Canada H2L 2W5.
Qi
S
S
Xu
D
D
Daloze
P
P
Chen
H
H
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D003602:Cytotoxicity, Immunologic / Q000187:drug effects; D004359:Drug Therapy, Combination; D006085:Graft Survival / Q000187:drug effects*; D000882:Haplorhini; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D016030:Kidney Transplantation / Q000276:immunology*; D008213:Lymphocyte Activation / Q000187:drug effects; D023421:Models, Animal; D020123:Sirolimus / Q000627:therapeutic use*; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects / Q000276:immunology*; D016559:Tacrolimus / Q000627:therapeutic use*; D018417:Th1 Cells / Q000187:drug effects / Q000276:immunology; D018418:Th2 Cells / Q000187:drug effects / Q000276:immunology; D013997:Time Factors; D014184:Transplantation, Homologous / Q000276:immunology*
D007166:Immunosuppressive Agents; D020123:Sirolimus; D016559:Tacrolimus