Mycophenolic acid derivative 118 improves outcome of skin grafts by suppressing IL-17 production

• Published in: Acta pharmacologica Sinica 2013-07, Vol.34 (7), p.921-929
• Main Authors: Kong, Fang-yuan, Chen, Wei, He, Shi-jun, Lin, Ze-min, Li, Xin, Zhang, Xiao-hui, Yang, Xiao-qian, Zhu, Feng-hua, Tong, Xian-kun, Zhou, Yu, Tang, Wei, Duan, Wen-hu, Zuo, Jian-ping
• Format: Article
• Language: English
• Subjects: Animals; Biomedical and Life Sciences; Biomedicine; CD4-Positive T-Lymphocytes - cytology; CD4-Positive T-Lymphocytes - drug effects; CD4-Positive T-Lymphocytes - immunology; Cell Differentiation - drug effects; Cell Differentiation - immunology; Coculture Techniques; Female; Graft Survival - drug effects; Graft Survival - immunology; Immunology; Interleukin-17 - antagonists & inhibitors; Interleukin-17 - biosynthesis; Interleukin-17 - secretion; Internal Medicine; Medical Microbiology; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mycophenolic Acid - pharmacology; Original; original-article; Pharmacology/Toxicology; Skin Transplantation - methods; Treatment Outcome; Vaccine
• ISSN: 1671-4083; 1745-7254
• DOI: 10.1038/aps.2013.14

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.