title: [The therapeutic mechanisms of sirolimus treatment for ischemic-type biliary lesions after liver transplantation].
abstract: OBJECTIVE
  To investigate the pathogenesis of ischemic-type biliary lesions (ITBLs) in post-liver transplant patients and the possible therapeutic mechanisms of sirolimus.
  
  
  METHODS
  The clinic data of 32 post-liver transplant patients with ITBLs from May 2004 to December 2010 was analyzed. There were including 25 male and 7 female patients with a median age of 46 years (ranging from 19 to 61 years). Patients were divided into those who received sirolimus (sirolimus group) and those who did not (control group). The expression of IL-2, FoxP3, and IL-10 in the portal area, liver function indexes, and bile duct injury score were assessed pre-ITBL, when ITBLs were identified, and after 6 months of sirolimus treatment.
  
  
  RESULTS
  Compared with pre-ITBL optical density (OD) values, there was a significantly increase in IL-2 OD(0.138 ± 0.050 in control group and 0.141 ± 0.052 in sirolimus group), but not FoxP3 and IL-10 OD in both groups at the time ITBLs were diagnosed. After 6 months of treatment, the IL-2, FoxP3, and IL-10 OD values in the control group were not different from those when ITBLs were diagnosed. There was a significant reduction in post-therapy IL-2 OD(0.107 ± 0.043, t = 2.087, P = 0.044), and a significant elevation in FoxP3(0.213 ± 0.039) and IL-10 OD(0.187 ± 0.048) in sirolimus group as compared with those when ITBLs were diagnosed(t = -3.822 and -4.350, both P < 0.01). There was a significant increase in serum levels of ALT, AST, total bilirubin, γ-glutamyl transpeptidase and ALP at the time ITBLs were diagnosed compared with pre-ITBL levels in both groups. After 6 months of treatment, the above indexes had not changed in the control group, but significantly improved in the sirolimus group, and the bile duct injury score in the sirolimus group had significantly decreased(4.4 ± 2.4, Z = -2.568, P = 0.010). The 1-year and 3-year graft survival rates in the control group were 6/13 and 5/13, respectively, and 17/19 and 13/19, respectively, in the sirolimus group (χ(2) = 7.166, P = 0.007; χ(2) = 5.398, P = 0.020, respectively).
  
  
  CONCLUSIONS
  Sirolimus can downregulate IL-2 expression and upregulate FoxP3 and IL-10 expression, thereby stimulating FoxP3+ Treg cells, suppressing immunopathological damage, and promoting epithelial repair in bile ducts.
authors.affiliation: Center of Liver Transplantation, Beijing Youan Hospital, Capital Medical University, Beijing 100069, China.
authors.forename: Chuan-yun
authors.initials: CY
authors.lastname: Li
authors.forename: Shi-chun
authors.initials: SC
authors.lastname: Lu
authors.forename: Wei
authors.initials: W
authors.lastname: Lai
authors.forename: Yuan
authors.initials: Y
authors.lastname: Liu
authors.forename: Tao-bing
authors.initials: TB
authors.lastname: Zeng
authors.forename: Qing-liang
authors.initials: QL
authors.lastname: Guo
authors.forename: Dong-dong
authors.initials: DD
authors.lastname: Lin
authors.forename: Ju-shan
authors.initials: JS
authors.lastname: Wu
authors.forename: Meng-long
authors.initials: ML
authors.lastname: Wang
authors.forename: Ning
authors.initials: N
authors.lastname: Li
mesh_terms: D000328:Adult; D001649:Bile Duct Diseases / Q000188:drug therapy*; D005260:Female; D051858:Forkhead Transcription Factors / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D016753:Interleukin-10 / Q000378:metabolism; D007376:Interleukin-2 / Q000378:metabolism; D007511:Ischemia / Q000178:diet therapy*; D016031:Liver Transplantation; D008297:Male; D008875:Middle Aged; D011183:Postoperative Complications / Q000188:drug therapy*; D020123:Sirolimus / Q000627:therapeutic use*; D055815:Young Adult
chemical_list: C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; C508609:IL10 protein, human; C508594:IL2 protein, human; D007376:Interleukin-2; D016753:Interleukin-10; D020123:Sirolimus