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Acute phase T cell help in neutrophil-mediated clearance of Helicobacter pylori.

机译:急性T细胞有助于中性粒细胞介导的幽门螺杆菌清除。

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摘要

Helicobacter pylori is a bacterium that inhabits the gastric mucosa and may cause ulcers and cancer. A vaccine is desirable because treatments are complex and impractical for endemic areas. CD4+ T cells are necessary for protection in mouse vaccination models, but little is known about which immune cells kill the bacteria and how T cells may mediate this. We therefore investigated a possible IL-17-CXC chemokine pathway of neutrophil recruitment and the requirement of neutrophils for protection. We stimulated CD4+ splenocytes with H. pylori-pulsed antigen presenting cells and analyzed supernatants for IL-17. We then treated cell populations with IL-17 to evaluate their production of KC, MIP-2, and LIX. Stomach biopsies were analyzed for bacterial load, inflammation, T cells, neutrophils, and cytokines in a kinetic study of days 1-13 post-infection. Additionally, we used IL-17, IL-17R, and CXCR2 knockout mice in immunization studies and performed an in vivo neutrophil depletion with immunized/challenged G-CSF-/- mice. We observed a robust IL-17 response in vitro with stimulated CD4+ cells, and IL-17 treatment of fibroblasts and epithelial cells induced KC and LIX secretion. Likewise, there were significant T cells and IL-17 expression beginning at day 3 in the kinetic study for immunized/challenged mice. There were significantly higher mRNA levels of KC, MIP-2, and LIX in immunized mice for days 5-13. Immunized mice had significantly higher inflammation and neutrophils by day 5, preceding the significantly lower bacterial load by day 7. Surprisingly, we did not observe changes in protection in our immunized IL-17-/- and IL-17R-/- mice. Immunized CXCR2-/- mice were also protected from infection but did have significant gastric neutrophil infiltration. The depletion of neutrophils from G-CSF-/- mice resulted in decreased peripheral and gastric neutrophils and in significantly elevated bacterial load. In conclusion, we observed a robust IL-17 response in our immunization model, and IL-17 induced a strong chemokine response for neutrophil recruitment. This cytokine alone, however, was not required for protection. Our findings suggest that there are compensatory mechanisms for protection and neutrophil recruitment in the absence of an IL-17-CXC chemokine pathway but that neutrophils do contribute significantly to bacterial clearance.
机译:幽门螺杆菌是一种居住在胃粘膜中的细菌,可能引起溃疡和癌症。疫苗是理想的,因为对于地方病地区,治疗方法复杂且不切实际。 CD4 + T细胞对于在小鼠疫苗接种模型中进行保护至关重要,但是对于哪些免疫细胞会杀死细菌以及T细胞如何介导这种细菌知之甚少。因此,我们研究了嗜中性粒细胞募集的可能的IL-17-CXC趋化因子途径和中性粒细胞的保护需求。我们用幽门螺杆菌脉冲的抗原呈递细胞刺激了CD4 +脾细胞,并分析了IL-17的上清液。然后,我们用IL-17处理细胞群体,以评估其KC,MIP-2和LIX的产生。在感染后1-13天的动力学研究中分析了胃活检的细菌载量,炎症,T细胞,中性粒细胞和细胞因子。此外,我们在免疫研究中使用了IL-17,IL-17R和CXCR2敲除小鼠,并用免疫/激发的G-CSF-/-小鼠进行了体内嗜中性白细胞耗竭。我们在体外观察到了刺激的CD4 +细胞对IL-17的强烈反应,成纤维细胞和上皮细胞的IL-17治疗诱导KC和LIX分泌。同样,在动力学研究中,免疫/激发小鼠的第3天开始有明显的T细胞和IL-17表达。在第5-13天,免疫小鼠的KC,MIP-2和LIX mRNA水平明显升高。到第5天,免疫小鼠的炎症和嗜中性粒细胞显着升高,而到第7天细菌负荷显着降低。令人惊讶的是,我们没有观察到免疫的IL-17-/-和IL-17R-/-小鼠的保护作用发生变化。免疫的CXCR2-/-小鼠也被保护免受感染,但是确实有明显的胃中性粒细胞浸润。 G-CSF-/-小鼠中性粒细胞的耗竭导致外周和胃中性粒细胞减少,细菌载量显着升高。总之,我们在免疫模型中观察到了强烈的IL-17反应,并且IL-17诱导了中性粒细胞募集的强烈趋化因子反应。然而,单独的这种细胞因子并不是保护所必需的。我们的发现表明,在不存在IL-17-CXC趋化因子途径的情况下,存在保护和中性粒细胞募集的补偿机制,但中性粒细胞确实对细菌清除有显着贡献。

著录项

  • 作者单位

    Case Western Reserve University.;

  • 授予单位 Case Western Reserve University.;
  • 学科 Health Sciences Pathology.;Health Sciences Immunology.
  • 学位 Ph.D.
  • 年度 2010
  • 页码 118 p.
  • 总页数 118
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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