OPS-2071（炎症性肠病的候选疗法）的抗菌和免疫抑制作用。,Digestive Diseases and Sciences

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OPS-2071（炎症性肠病的候选疗法）的抗菌和免疫抑制作用。
Digestive Diseases and Sciences ( IF 2.5 ) Pub Date : 2021-08-31 , DOI: 10.1007/s10620-021-07237-2
Masayoshi Sato ₁ , Kazuyuki Fujii ₁ , Hiroko Takagi ₁ , Isao Shibuya ₁ , Daisuke Oka ₁ , Naomitsu Yamaya ₂ , Hiraku Hagita ₂ , Makoto Matsumoto ₃ , Katsuya Inagaki ₁

Affiliation

背景炎症性肠病(IBD)是胃肠道的慢性炎症性疾病。尽管使用了许多类型的药物，但临床结果仍不能令人满意。以前的研究表明肠道细菌参与了IBD的发病机制。因此，在 IBD 模型中，我们评估了 OPS-2071（一种用于肠道感染的低吸收喹诺酮类抗菌剂）的治疗效果，并研究了其作用机制。方法使用幼稚CD4 + T细胞转移IBD模型小鼠评估OPS-2071和比较疗法的治疗效果。使用小鼠脾细胞和人外周血单核细胞评估 LPS 诱导的 TNF-α 产生的体外抑制和对使用抗 CD3/CD28 抗体负载珠刺激的 T 细胞反应的抑制作用。此外，还测试了针对与 IBD 发病机制有关的细菌的体外活性。结果与载体组相比，OPS-2071 剂量依赖性地降低了结肠重量/长度比和结肠炎组织学评分。OPS-2071 的治疗效果与抗 IL-12/23 (p40) 抗体相当。在体外，OPS-2071 以剂量依赖性方式抑制 LPS 刺激和 T 细胞反应诱导的 TNF-α 产生。在高浓度下，这些作用与现有的免疫抑制剂（如泼尼松龙）在小鼠和人类细胞中的作用相当。OPS-2071 还显示出对 IBD 相关细菌的抗菌活性。结论我们的结果表明 OPS-2071 具有免疫抑制和抗菌作用。这种双重效应使 OPS-2071 成为 IBD 的独特且有希望的候选者。

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Antibacterial and Immunosuppressive Effects of OPS-2071, a Candidate Therapy for Inflammatory Bowel Disease.

BACKGROUND Inflammatory bowel disease (IBD) is a chronic inflammatory disease of the gastrointestinal tract. Although many types of drug are used, clinical outcomes are still unsatisfactory. Previous studies have suggested that intestinal bacteria are involved in the pathogenesis of IBD. Accordingly, in an IBD model we evaluated the therapeutic effects of OPS-2071, a low-absorption quinolone antibacterial agent indicated for intestinal infection, and investigated its mechanism of action. METHODS The therapeutic effects of OPS-2071 and comparison therapies were evaluated using naive CD4 + T cell-transfer IBD model mice. In vitro inhibition of LPS-induced TNF-α production and inhibitory effects on T cell responses stimulated using anti-CD3/CD28 antibody-loaded beads were evaluated using mouse splenocytes and human peripheral blood mononuclear cells. In addition, in vitro activities against bacteria implicated in IBD pathogenesis were tested. RESULTS OPS-2071 dose-dependently decreased both colonic weight/length ratio and the colitis histological score as compared with the vehicle group. The therapeutic effect of OPS-2071 was equivalent to that of anti-IL-12/23 (p40) antibody. In vitro, OPS-2071 suppressed TNF-α production induced by LPS stimulation and T cell responses in a dose-dependent manner. At high concentrations, these effects were comparable to those of existing immunosuppressive agents, such as prednisolone, in both mouse and human cells. OPS-2071 also showed antibacterial activity against IBD-related bacteria. CONCLUSIONS Our results suggest that OPS-2071 had both immunosuppressive and antibacterial effects. This dual effect makes OPS-2071 a unique and promising candidate for IBD.

更新日期：2021-08-31

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