Abstract
Aim:
To investigate the effects and underlying mechanisms of 118, a novel derivative of mycophenolic acid, in a murine allogeneic skin graft model.
Methods:
Skin grafts were conducted by grafting BALB/c donor tail skin into C57BL/6 skin beds (allograft) or by grafting female C57BL/6 donor tail skin into female C57BL/6 skin beds (syngraft). The mice were treated with the derivative 118 (40 mg·kg−1·d−1, po) for 13 d (3 d before and 10 d after transplantation). Skin grafts, splenocytes and graft-infiltrated lymphocytes were isolated and examined ex vivo. The effects of the derivative 118 on naive CD4+ T cell differentiation were examined in vitro.
Results:
Treatment with the derivative 118 dramatically increased the survival rate of murine allogeneic skin grafts. Flow cytometric analysis and H&E staining showed that the derivative significantly decreased inflammatory cell infiltration into the grafts. The levels of the chemokines CXCL1, CXCL2, CCL7, and CCL2 were reduced in the derivative 118-treated grafts. Additionally, the derivative 118 significantly suppressed the IL-17 levels in the grafts but did not affect the differentiation of systemic helper T cells in the murine allogeneic skin graft model. Furthermore, IL-23p19 expression was suppressed in the grafts from the derivative 118-treated group, which might be due to decreases in TLR4 and MyD88 expression. Finally, the derivative 118 did not exert direct influences on helper T cell differentiation in vitro.
Conclusion:
Treatment with the mycophenolic acid derivative 118 improves murine allogeneic skin grafts by decreasing IL-23 expression and suppressing local IL-17 secretion in the grafts, rather than directly inhibiting Th17 differentiation.
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Acknowledgements
This work was supported by grants from the National Natural Science Foundation of China (NSFC) (Nos 81072652, 81273524, and 81273525).
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Kong, Fy., Chen, W., He, Sj. et al. Mycophenolic acid derivative 118 improves outcome of skin grafts by suppressing IL-17 production. Acta Pharmacol Sin 34, 921–929 (2013). https://doi.org/10.1038/aps.2013.14
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DOI: https://doi.org/10.1038/aps.2013.14
