title: Mycophenolic acid derivative 118 improves outcome of skin grafts by suppressing IL-17 production.
abstract: OBJECTIVE
  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.
  
  
  CONCLUSIONS
  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.
authors: State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, China.
authors: Fang-yuan
authors: FY
authors: Kong
authors: Wei
authors: W
authors: Chen
authors: Shi-jun
authors: SJ
authors: He
authors: Ze-min
authors: ZM
authors: Lin
authors: Xin
authors: X
authors: Li
authors: Xiao-hui
authors: XH
authors: Zhang
authors: Xiao-qian
authors: XQ
authors: Yang
authors: Feng-hua
authors: FH
authors: Zhu
authors: Xian-kun
authors: XK
authors: Tong
authors: Yu
authors: Y
authors: Zhou
authors: Wei
authors: W
authors: Tang
authors: Wen-hu
authors: WH
authors: Duan
authors: Jian-ping
authors: JP
authors: Zuo
mesh_terms: D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D002454:Cell Differentiation / Q000187:drug effects / Q000276:immunology; D018920:Coculture Techniques; D005260:Female; D006085:Graft Survival / Q000187:drug effects* / Q000276:immunology; D020381:Interleukin-17 / Q000037:antagonists & inhibitors* / Q000096:biosynthesis* / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009173:Mycophenolic Acid / Q000494:pharmacology*; D016038:Skin Transplantation / Q000379:methods*; D016896:Treatment Outcome
chemical_list: D020381:Interleukin-17; D009173:Mycophenolic Acid
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