Li Chuan-yun, Lu Shi-chun, Lai Wei, Liu Yuan, Zeng Tao-bing, Guo Qing-liang, Lin Dong-dong, Wu Ju-shan, Wang Meng-long, Li Ning
Center of Liver Transplantation, Beijing Youan Hospital, Capital Medical University, Beijing 100069, China.
Zhonghua Wai Ke Za Zhi. 2013 Aug;51(8):691-5.
To investigate the pathogenesis of ischemic-type biliary lesions (ITBLs) in post-liver transplant patients and the possible therapeutic mechanisms of sirolimus.
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.
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).
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.
探讨肝移植术后患者缺血型胆管病变（ITBLs）的发病机制及西罗莫司可能的治疗机制。
分析2004年5月至2010年12月32例肝移植术后发生ITBLs患者的临床资料。其中男性25例，女性7例，中位年龄46岁（19至61岁）。患者分为接受西罗莫司治疗者（西罗莫司组）和未接受者（对照组）。在ITBLs发生前、确诊时以及西罗莫司治疗6个月后，评估门管区IL-2、FoxP3和IL-10的表达、肝功能指标及胆管损伤评分。
与ITBLs发生前光密度（OD）值相比，两组在ITBLs确诊时IL-2 OD显著升高（对照组为0.138±0.050，西罗莫司组为0.141±0.052），但FoxP3和IL-10 OD无变化。治疗6个月后，对照组IL-2、FoxP3和IL-10 OD值与ITBLs确诊时相比无差异。西罗莫司组治疗后IL-2 OD显著降低（0.107±0.043，t = 2.087，P = 0.044），FoxP3（0.213±0.039）和IL-10 OD（0.187±0.048）与ITBLs确诊时相比显著升高（t = -3.822和-4.350，P均<0.01）。两组在ITBLs确诊时血清ALT、AST、总胆红素、γ-谷氨酰转肽酶和ALP水平较ITBLs发生前均显著升高。治疗6个月后，对照组上述指标无变化，而西罗莫司组显著改善，且西罗莫司组胆管损伤评分显著降低（4.4±2.4，Z = -2.568，P = 0.010）。对照组1年和3年移植物存活率分别为6/13和5/13，西罗莫司组分别为17/19和13/19（χ(2) = 7.166，P = 0.007；χ(2) = 5.398，P = 0.020）。
西罗莫司可下调IL-2表达，上调FoxP3和IL-10表达，从而刺激FoxP3+调节性T细胞，抑制免疫病理损伤，促进胆管上皮修复。
