Approaches To Immunological Intervention In Schistosomiasis

血吸虫病的免疫干预方法

• 批准号: 7592235
• 负责人: Thomas Wynn
• 金额: $ 189.98万
• 依托单位: NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7592235
• 关键词: Acute; Affect; Animals; Cellularity; Chronic; Data; Development; Disease; Exhibits; Family; Fibrosis; Goals; Granuloma; Granulomatous; Human; Hydroxyproline; Immune; Immune response; Individual; Infection; Inflammation; Interleukin-10; Interleukin-13; Interleukin-4; Interleukin-5; Interleukin-9; Intestines; Knockout Mice; Lead; Lesion; Liver; Liver Fibrosis; Measures; Mediating; Modeling; Molecular; Monitor; Morbidity - disease rate; Mus; Parasites; Pathogenesis; Pathology; Phase; Phenotype; Portal Hypertension; Portal Venous System; Process; Research; Risk; Role; Schistosoma; Schistosoma mansoni; Schistosoma mansonii infection; Schistosomiasis; Time; Transgenic Organisms; Week; base; cytokine; egg; immunological intervention; inhibitor/antagonist; interleukin-17C; interleukin-21; mortality; programs; receptor; research study; size

IL-13Ra2 and IL-10 were shown to coordinately suppress the development of hepatic fibrosis following Schistosoma mansoni infection in mice: To investigate the functional role of IL-10 and IL-13Ra2 in a chronic model of fibrosis, mice were infected with 30 cercariae of S. mansoni and granuloma formation and fibrosis were assessed at acute (8 wk) and chronic time points (12 wk) post infection. At week 8 pi, deletion of IL-13Ra2 or IL-10 had little impact on granuloma size or on the cellularity of the lesions. However, granuloma size was exacerbated in mice that were deficient in both IL-10 and IL-13Ra2 (dKO mice) (30% increase versus WT), which suggested that IL-10 and IL-13Ra2 function as cooperative inhibitors of granulomatous inflammation, at least during the acute phase of infection. By week 12, IL-10-/- and IL-13Ra2-/- mice also displayed significantly larger granulomas. Indeed, while WT mice displayed a 20% decrease in granuloma size between wk 8 and 12, IL-10-/- and IL-13Ra2-/- mice exhibited significantly larger granulomas at the chronic time point. The granulomas in dKO mice were approximately 50% larger than WT animals on wk 12 and 20-30% larger than either single KO mice. The progression of liver fibrosis was also monitored by measuring hydroxyproline content in the liver. On wk 8, liver fibrosis was similar in WT and IL-13Ra2-/- mice, but significantly decreased in IL-10-/- mice. Thus, despite displaying signficant inflammation, many other pathological features were reduced in the IL-10-/- mice. The important contribution of IL-13Ra2 was revealed in the dKO mice, which in contrast to IL-10-/- mice developed exacerbated liver fibrosis as early as wk 8 p.i. Thus, deleting IL-13Ra2 on an IL-10-/- background completely reversed the pathological phenotype of the IL-10-/- mice. The combined anti-fibrotic activities of IL-10 and IL-13Ra2 were particularly impressive at the chronic time point. Indeed, by wk 12, fibrosis nearly doubled in the dKO mice when compared with 12 wk-infected WT, IL-10-/- or IL-13Ra2-/- mice. These data demonstrate that chronic Th2-mediated inflammation and fibrosis are down modulated by the combined actions of IL-10 and IL-13Ra2.

IL-13RA2和IL-10被证明可以协同抑制小鼠曼氏血吸虫感染后肝纤维化的发展： 为了研究IL-10和IL-13RA2在纤维化的慢性模型中的功能作用，在感染后感染后，在急性（8周）和慢性时间点（8周）和慢性时间点（8周）和慢性时间点（8周）和纤维化评估了30小鼠和肉芽肿的形成和纤维化。 在第8周PI时，IL-13RA2或IL-10的缺失对肉芽瘤大小或病变的细胞性影响很小。然而，在IL-10和IL-13RA2（DKO小鼠）中缺乏缺乏的小鼠中，肉芽肿大小加剧（与WT相比30％），这表明IL-10和IL-13RA2在急性阶段受到急性阶段的颗粒炎症的合作抑制剂，至少在急性阶段受到刺激性阶段。到第12周，IL-10 - / - 和IL-13RA2 - / - 小鼠也显示出明显更大的肉芽肿。实际上，尽管WT小鼠在WK 8和12之间的粒率降低了20％，而IL-10 - / - 和IL-13RA2 - / - 小鼠在慢性时点表现出明显更大的肉芽肿。在WK 12和20-30％的DKO小鼠中，DKO小鼠的肉芽肿大约比任何一个KO小鼠大50％。 还通过测量肝脏中的羟丙烯含量来监测肝纤维化的进展。在WK 8上，WT和IL-13RA2 - / - 小鼠的肝纤维化相似，但在IL-10 - / - 小鼠中显着降低。因此，尽管表现出引人注目的炎症，但在IL-10 - / - 小鼠中降低了许多其他病理特征。在DKO小鼠中揭示了IL-13RA2的重要贡献，与IL-10 - / - 小鼠相反，它早在WK 8 P.I时就会发出加剧的肝纤维化。因此，在IL-10 - / - 背景上删除IL-13RA2完全逆转了IL-10 - / - 小鼠的病理表型。 在慢性时点，IL-10和IL-13RA2的抗纤维化活性的组合尤其令人印象深刻。实际上，通过WK 12，与12周感染的WT，IL-10 - / - 或IL-13RA2-/ - 小鼠相比，DKO小鼠的纤维化几乎翻了一番。 这些数据表明，慢性Th2介导的炎症和纤维化受到IL-10和IL-13RA2的综合作用的调节。