Approaches To Immunological Intervention In Schistosomiasis

血吸虫病的免疫干预方法

• 批准号: 8555835
• 负责人: Thomas Wynn
• 金额: $ 92.18万
• 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/8555835
• 关键词: Acute; Affect; Anemia; Area; Ascites; CCL17 gene; CCL4 gene; CD4 Positive T Lymphocytes; Cell secretion; Chronic; Chronic Disease; Cirrhosis; Data; Dendritic Cells; Dendritic cell activation; Development; Disease; Enzymes; Esophageal and Gastric Varices; Family; Feedback; Fibrosis; G Protein-Coupled Receptor Signaling; GPR2 gene; Goals; Granuloma; Granulomatous; Helminths; Hemorrhage; Hepatosplenomegaly; Human; Immune; Immune response; In Vitro; Individual; Infection; Inflammation; Insulin-Like Growth Factor I; Interferons; Interleukin 4 Receptor; Interleukin-10; Interleukin-12; Interleukin-13; Interleukin-17; Interleukin-4; Interleukin-5; Interleukin-9; Interleukins; Intestines; Knockout Mice; Larva; Lead; Liver; Liver Fibrosis; Liver diseases; Lung; Lung Inflammation; Mediating; Mediator of activation protein; Messenger RNA; Modeling; Molecular; Morbidity - disease rate; Mus; Parasites; Parasitic nematode; Pathogenesis; Pathology; Patients; Pattern; Pneumonia; Population; Portal Hypertension; Portal Venous System; Process; Production; Proteins; RGS Proteins; Reagent; Receptor Signaling; Research; Resolution; Risk; Role; Schistosoma; Schistosoma mansoni; Schistosome Granuloma; Schistosomiasis; Signal Transduction Pathway; T-Lymphocyte; Th2 Cells; Thrombocytopenia; Tissues; Transgenic Mice; Wild Type Mouse; Work; Wound Healing; base; cell mediated immune response; chemokine; cytokine; egg; gastrointestinal; immunological intervention; in vivo; interleukin-17B; interleukin-21; macrophage; mortality; neutralizing antibody; pathogen; pathogen exposure; programs; pulmonary granuloma; receptor; research study; response; trafficking

In schistosomiasis, the pathology resulting from chronic infection is predominantly induced by the host immune response to parasite eggs that are laid, in the case of Schistosoma mansoni, in the portal venous system and subsequently trapped in the liver and intestine. The egg induced granulomatous response eventually triggers significant liver fibrosis, which is the primary cause of chronic morbidity and mortality. Our work is focused on elucidating the mechanisms of granulomatous inflammation and fibrosis. Progress was made in the following areas: 1) Interleukin-4 is a cytokine widely known for its role in CD4(+) T cell polarization and its ability to alternatively activate macrophage populations. In contrast, the impact of IL-4 on the activation and function of dendritic cells (DCs) during helminth infection is poorly understood. We found that DCs respond to IL-4 both in vitro and in vivo by expression of multiple alternative activation markers with a different expression pattern to that of macrophages. We further demonstrate a central role for DC IL-4Rα expression in the optimal induction of IFNγ responses in vivo in both Th1 and Th2 settings, through a feedback loop in which IL-4 promotes DC secretion of IL-12. Finally, we revealed a central role for RELMα during T-cell priming, establishing that its expression by DCs is critical for optimal IL-10 and IL-13 promotion in vitro and in vivo. Together, these data highlight the significant impact that IL-4 and RELMα can have on DC activation and function in the context of either bacterial or helminth pathogens. 2) The regulators of G protein signaling (RGS) protein superfamily negatively controls G protein-coupled receptor signal transduction pathways. RGS16 is enriched in activated/effector T lymphocytes. We show that RGS16 constrains pulmonary inflammation by regulating chemokine-induced T cell trafficking in response to challenge with Schistosoma mansoni. Upon pathogen exposure, Rgs16(-/-) mice developed more robust granulomatous lung fibrosis than wild-type counterparts. Distinct Th2 or putative Th17 subsets expressing CCR4 or CCR10 accumulated more rapidly in Rgs16(-/-) lungs following challenge and produced proinflammatory cytokines IL-13 and IL-17B. CCR4(+)Rgs16(-/-) Th2 cells migrated excessively to CCL17 and localized aberrantly in challenged lungs. T lymphocytes were partially excluded from lung granulomas in Rgs16(-/-) mice, instead forming peribronchial/ perivascular aggregates. Thus, RGS16-mediated confinement of T cells to Schistosome granulomas mitigates widespread cytokine-mediated pulmonary inflammation. 3) Helminths induce potent T helper 2 (TH2)-type immune responses that can mediate worm expulsion, but the role of this response in controlling the acute tissue damage caused by migrating multicellular parasites through vital tissues remains uncertain. We used a helminth infection model in which parasitic nematode larvae migrate transiently through the lung, resulting in hemorrhage and inflammation. We found that IL-17 initially contributed to inflammation and lung damage, whereas subsequent IL-4 receptor (IL-4R) signaling reduced elevations in IL-17 mRNA levels, enhanced the expression of insulin-like growth factor 1 (IGF-1) and IL-10 and stimulated the development of M2 macrophages, all of which contributed to the rapid resolution of tissue damage. These studies indicate an essential role for TH2-type immune responses in mediating acute wound healing during helminth infection. 4) 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.

在血吸虫病中，慢性感染引起的病理主要是由宿主免疫反应对寄生虫卵的免疫反应，而在门户静脉系统中，寄生的寄生虫卵，随后被困在肝脏和纯直的情况下。卵引起的肉芽肿反应最终会触发明显的肝纤维化，这是慢性发病率和死亡率的主要原因。我们的工作重点是阐明肉芽肿性炎症和纤维化的机制。在以下领域取得了进展： 1）白介素-4是一种以CD4（+）T细胞极化及其替代激活巨噬细胞群体的能力而闻名的细胞因子。相反，对蠕虫感染期间树突状细胞（DC）的激活和功能的影响很少了解。我们发现DC通过表达多种替代激活标记物具有与巨噬细胞不同的表达模式来对IL-4响应IL-4。我们进一步证明了DC IL-4Rα表达在TH1和TH2设置中通过IL-4促进IL-12的DC分泌的反馈回路，在TH1和TH2设置中的IFNγ响应最佳诱导中的核心作用。最后，我们揭示了在T细胞启动过程中RERMα的核心作用，确定其DC的表达对于最佳的IL-10和IL-13促进体外和体内至关重要。这些数据共同凸显了IL-4和RERMα在细菌或蠕虫病原体的背景下对DC激活和功能产生的显着影响。 2）G蛋白信号传导（RGS）蛋白超家族的调节剂对G蛋白偶联受体信号转导途径进行负面影响。 RGS16富含活化/效应的淋巴细胞。我们表明，RGS16通过调节趋化因子诱导的T细胞运输以响应曼氏菌的挑战来限制肺部炎症。病原体暴露后，RGS16（ - / - ）小鼠比野生型对应物发展出更健壮的肉芽肿肺纤维化。表达CCR4或CCR10的独特的Th2或推定的TH17子集在挑战后RGS16（ - / - ）肺部积聚，并产生促炎细胞因子IL-13和IL-17B。 CCR4（+）RGS16（ - / - ）TH2细胞过度迁移至CCL17，并在受挑战性的肺部异常局部局部。在RGS16（ - / - ）小鼠中，将T淋巴细胞部分排除在肺肉芽肿中，而不是形成周围/血管周围聚集体。因此，RGS16介导的T细胞与黑素肉芽肿的限制减轻了广泛的细胞因子介导的肺部炎症。 3）蠕虫诱导有效的T辅助器2（TH2） - 型免疫反应，可以介导蠕虫驱动，但是这种反应在控制通过重要组织通过迁移多细胞寄生虫造成的急性组织损伤的作用仍然不确定。我们使用了蠕虫线虫幼虫在肺部瞬时迁移，导致出血和炎症。我们发现，IL-17最初导致炎症和肺损伤，而随后的IL-4受体（IL-4R）信号传导降低了IL-17 mRNA水平的升高，增强了胰岛素样生长因子1（IGF-1）和IL-10和IL-10的表达，并刺激了M2巨噬细胞的发展，并刺激了对当时造成的造成损害的造成损害的造成损害。这些研究表明，Th2型免疫反应在介导蠕虫感染期间急性伤口愈合中的重要作用。 4）进行性纤维化有助于几种慢性疾病的发病率；它通常会缓慢发展，因此控制其进展和分辨率的机制很难建模。蛋白质白介素（IL）-10，IL-12P40和IL-13Rα2在感染了helminth寄生虫分烟瘤后调节肝纤维化。我们检查了这些介体是否相互作用以减慢血吸虫病小鼠肝纤维化的进展。 IL-10（ - / - ），IL-12/23（P40）（ - / - ）和IL-13Rα2（ - / - ）小鼠交叉以产生三重敲除（TKO）小鼠。我们研究了这些小鼠，以确定在感染了S Mansoni后感染后，免疫反应的这3个阴性调节因子是否同时删除了肝纤维化的死亡率。与野生型小鼠相比，TKO小鼠在S Mansoni，肝纤维化和死亡率中诱导炎症大大增加。 TKO小鼠的100％在感染后10周死亡。发病率和死亡率与门户高血压，肝肾上腺全球，胃肠道出血，腹水，血小板减少症，食管和胃静脉曲张，贫血以及肝酶的水平增加有关IL-10，IL-12P40和IL-13Rα2降低了纤维化细胞因子IL-13的产生和活性。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。 S Mansoni感染后，IL-10，IL-12P40和IL-13Rα2作用着抑制小鼠的肝纤维化。该模型迅速再现了晚期肝硬化患者中观察到的许多并发症，因此它可用于评估针对血吸虫病或与T-Helper 2细胞2细胞介导的免疫反应相关的血吸虫病或其他纤维化疾病开发的抗纤维化试剂的疗效。