2010 - TTS International Congress


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T Cell Diversity and Functional Biology

87.8 - Contribution of regulatory T cells combined with low-dose Sirolimus, but not Tacrolimus, to delay acute rejection of renal allografts in cynomolgus monkeys

Presenter: Huifang, Chen, Montreal, Canada
Authors: Ma A., Song L., Qi S., Hu Y., Dun H., Xiong Z., Daloze P., Chen H.

CONTRIBUTION OF REGULATORY T CELLS COMBINED WITH LOW-DOSE SIROLIMUS, BUT NOT TACROLIMUS, TO DELAY ACUTE REJECTION OF RENAL ALLOGRAFTS IN CYNOMOLGUS MONKEYS

T CELL DIVERSITY AND FUNCTIONAL BIOLOGY

A. Ma1, L. Song1, S. Qi1, Y. Hu1, H. Dun1, Z. Xiong1, P. Daloze2, H. Chen1
1Lab. Of Experimental Surgery, CHUM, Notre-Dame Hospital, University of Montreal, Montreal/QC/CANADA, 2Department Of Surgery, CHUM, Notre-Dame Hospital, University of Montreal, Montreal/CANADA

Body: CD4+CD25+ regulatory T (Treg) cells, like immunosuppressant, are potent suppressors, play an important role in organ transplantation and autoimmune diseases. Our previous study proved that Tregs play an important role in transplantation and autoimmune disease models. The aim of this study was to investigate the contribution of Tregs combined with sirolimus or tacrolimus to delay acute rejection of renal allografts in cynomolgus monkeys. Our studies showed that frequencies of CD4+ T cells with regulatory phenotype and function were significantly decreased in peripheral blood of renal transplant monkeys receiving tacrolimus compared with those receiving sirolimus. The percentages of splenic CD4+CD25high T cells were higher in monkeys treated with sirolimus alone and combined therapy of Tregs plus sirolimus, compared with naïve and tacrolimus-treated monkeys. CD4+CD25high T cells further increased in inferior mesenteric lymph nodes, of which the site was very close to renal allografts, from the recipients of long-term survival of renal allografts (> 180 days). CD4+CD25high, but not CD4+CD25-, T cells from all groups of kidney transplant recipients all expressed Foxp3, which expression was the higher in the group of combined therapy of Tregs plus sirolimus, and the lower in the group of tacrolimus alone. In vitro, splenic CD4+CD25+ T cells isolated from sirolimus-treated monkeys displayed a slight suppressive activity in the proliferation of auto-CD4+ T cells activated by TCR stimulation, but significantly increased in monkeys receiving combined therapy of Tregs plus sirolimus, compared with those from tacrolimus-treated monkeys. An increased population of CD4+IL-10+ Tr1 cells was detected in spleens from long-term survival recipients, but not in peripheral blood. The high production of Tr1 like cytokines, IL-10 and TGF-β, was found in splenic CD4+CD25+ T cells from the recipients of long-term survival of renal allografts, but lower in inferior mesenteric lymph nodes. Our results also indicated that S aureus Cowan I antigen-activated-CD19+ B cells isolated from the inferior mesenteric lymph nodes in tolerance monkeys expressed more CD25 than those from spleen or peripheral blood. Similar expression was found in BCR cross-linking. In vitro experiments, activated-CD19+CD25+ Bregs induced arrest of cell division on autologous CD4+ T effcetor cells and down-regulated CD4+ T cell proliferation in the presence of TCR stimulation. In conclusion, adoptive transfer of Tregs combined with low-dose sirolimus, but not tacrolimus preserves suppressive function of Tregs and delayed acute rejection of renal allografts in cynomolgus Monkeys.

Disclosure: All authors have declared no conflicts of interest.


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