<br>抗 HIV 候选药物 Abx464 通过触发激活的巨噬细胞产生 IL-22 来抑制肠道炎症。,Scientific Reports

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抗 HIV 候选药物 Abx464 通过触发激活的巨噬细胞产生 IL-22 来抑制肠道炎症。
Scientific Reports ( IF 3.8 ) Pub Date : 2017-07-07 , DOI: 10.1038/s41598-017-04071-3
Karim Chebli ₁ , Laura Papon ₁ , Conception Paul ₁ , Aude Garcel ₂ , Noëlie Campos ₂ , Didier Scherrer ₂ , Hartmut J Ehrlich ₂ , Michael Hahne ₁ , Jamal Tazi ₁

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人类免疫缺陷病毒（HIV）的进展与胃肠道（GI）粘膜损伤有关。这种损伤使得细菌从肠道移位并导致随后的炎症。葡聚糖硫酸钠（DSS-exposure）是一种已建立的实验性结肠炎动物模型，最近被证明可以概括胃肠道损伤与 SIV 感染致病特征之间的联系。目前的研究测试了 ABX464 的保护特性，ABX464 是目前处于 II 期临床试验的一流抗 HIV 候选药物。 ABX464 治疗可显着减轻 DSS 诱导的小鼠结肠炎，并在停药后对长期 DSS 暴露产生长期保护作用。一致地，ABX464 减少了结肠炎症细胞因子 IL-6 和 TNFα 以及趋化剂 MCP-1 的产生。然而，RNA 谱分析揭示了 ABX464 在 DSS 治疗的小鼠和 LPS 刺激的骨髓来源的巨噬细胞中诱导 IL-22 表达的能力，IL-22 是一种参与结肠炎组织修复的细胞因子。重要的是，抗 IL-22 抗体显着降低了 ABX464 对 DSS 治疗小鼠结肠炎的保护作用。由于肠道粘膜中 IL-22 产生的减少是 HIV 和 DSS 诱导的免疫发病机制的一个既定因素，因此我们的数据表明 ABX464 的抗炎特性值得在 HIV 和炎症性溃疡性结肠炎 (UC) 疾病中进行探索。

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The Anti-Hiv Candidate Abx464 Dampens Intestinal Inflammation by Triggering Il-22 Production in Activated Macrophages.

The progression of human immunodeficiency virus (HIV) is associated with mucosal damage in the gastrointestinal (GI) tract. This damage enables bacterial translocation from the gut and leads to subsequent inflammation. Dextran sulfate sodium (DSS-exposure) is an established animal model for experimental colitis that was recently shown to recapitulate the link between GI-tract damage and pathogenic features of SIV infection. The current study tested the protective properties of ABX464, a first-in-class anti-HIV drug candidate currently in phase II clinical trials. ABX464 treatment strongly attenuated DSS-induced colitis in mice and produced a long-term protection against prolonged DSS-exposure after drug cessation. Consistently, ABX464 reduced the colonic production of the inflammatory cytokines IL-6 and TNFα as well as that of the chemoattractant MCP-1. However, RNA profiling analysis revealed the capacity of ABX464 to induce the expression of IL-22, a cytokine involved in colitis tissue repair, both in DSS-treated mice and in LPS-stimulated bone marrow-derived macrophages. Importantly, anti-IL-22 antibodies significantly reduced the protective effect of ABX464 on colitis in DSS-treated mice. Because reduced IL-22 production in the gut mucosa is an established factor of HIV and DSS-induced immunopathogenesis, our data suggest that the anti-inflammatory properties of ABX464 warrant exploration in both HIV and inflammatory ulcerative colitis (UC) disease.

更新日期：2017-07-08

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