Program in Barrier Immunity and Repair, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, USA.
Gastroenterology. 2011 Dec;141(6):2200-9. doi: 10.1053/j.gastro.2011.08.008. Epub 2011 Aug 22.
BACKGROUND & AIMS: Progressive fibrosis contributes to the morbidity of several chronic diseases; it typically develops slowly, so the mechanisms that control its progression and resolution have been difficult to model. The proteins interleukin (IL)-10, IL-12p40, and IL-13Rα2 regulate hepatic fibrosis following infection with the helminth parasite Schistosoma mansoni. We examined whether these mediators interact to slow the progression of hepatic fibrosis in mice with schistosomiasis.
IL-10(-/-), IL-12/23(p40)(-/-), and IL-13Rα2(-/-) mice were crossed to generate triple knockout (TKO) mice. We studied these mice to determine whether the simultaneous deletion of these 3 negative regulators of the immune response accelerated mortality from liver fibrosis following infection with S mansoni.
Induction of inflammation by S mansoni, liver fibrosis, and mortality increased greatly in TKO mice compared with wild-type mice; 100% of the TKO mice died by 10 weeks after infection. Morbidity and mortality were associated with the development of portal hypertension, hepatosplenomegaly, gastrointestinal bleeding, ascites, thrombocytopenia, esophageal and gastric varices, anemia, and increased levels of liver enzymes, all features of advanced liver disease. IL-10, IL-12p40, and IL-13Rα2 reduced the production and activity of the profibrotic cytokine IL-13. A neutralizing antibody against IL-13 reduced the morbidity and mortality of the TKO mice following S mansoni infection.
IL-10, IL-12p40, and IL-13Rα2 act cooperatively to suppress liver fibrosis in mice following infection with S mansoni. This model rapidly reproduces many of the complications observed in patients with advanced cirrhosis, so it might be used to evaluate the efficacy of antifibrotic reagents being developed for schistosomiasis or other fibrotic diseases associated with a T-helper 2 cell-mediated immune response.
进行性纤维化是几种慢性疾病发病和致残的主要原因,它通常发展缓慢,因此控制其进展和消退的机制一直难以建模。白细胞介素 (IL)-10、IL-12p40 和 IL-13Rα2 可调节曼氏血吸虫感染后的肝纤维化,我们研究了这些介质是否相互作用以减缓感染曼氏血吸虫的小鼠肝纤维化的进展。
将 IL-10(-/-)、IL-12/23(p40)(-/-) 和 IL-13Rα2(-/-) 小鼠进行杂交以产生三重敲除 (TKO) 小鼠。我们研究了这些小鼠,以确定这些 3 种免疫反应负调节剂的同时缺失是否会加速感染曼氏血吸虫后肝纤维化导致的死亡率。
与野生型小鼠相比,TKO 小鼠的 S mansoni 诱导的炎症、肝纤维化和死亡率大大增加;感染后 10 周内,100%的 TKO 小鼠死亡。发病率和死亡率与门静脉高压、肝脾肿大、胃肠道出血、腹水、血小板减少、食管和胃静脉曲张、贫血以及肝酶水平升高有关,所有这些都是晚期肝病的特征。IL-10、IL-12p40 和 IL-13Rα2 降低了促纤维化细胞因子 IL-13 的产生和活性。针对 IL-13 的中和抗体可降低 S mansoni 感染后 TKO 小鼠的发病率和死亡率。
IL-10、IL-12p40 和 IL-13Rα2 共同作用以抑制感染 S mansoni 后的小鼠肝纤维化。该模型迅速再现了许多晚期肝硬化患者观察到的并发症,因此它可用于评估正在开发的用于血吸虫病或其他与辅助性 T 细胞 2 细胞介导的免疫反应相关的纤维化疾病的抗纤维化试剂的疗效。