Infectious Diseases Unit, Department of Medical Innovations, New Drug Research Division, Otsuka Pharmaceutical Co., Ltd, 463-10, Kagasuno, Kawauchi-cho, Tokushima-shi, Tokushima, 771-0192, Japan.
Department of Drug Metabolism and Pharmacokinetics, Otsuka Pharmaceutical Co., Ltd, 463-10, Kagasuno, Kawauchi-cho, Tokushima-shi, Tokushima, 771-0192, Japan.
Dig Dis Sci. 2022 Aug;67(8):3993-4007. doi: 10.1007/s10620-021-07237-2. Epub 2021 Aug 31.
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.
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.
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.
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.
炎症性肠病（IBD）是一种胃肠道的慢性炎症性疾病。尽管有许多类型的药物被用于治疗，但临床结果仍不理想。先前的研究表明，肠道细菌参与了 IBD 的发病机制。因此，我们在 IBD 模型中评估了低吸收喹诺酮类抗菌药物 OPS-2071 的治疗效果，并研究了其作用机制。
使用幼稚 CD4+T 细胞转移 IBD 模型小鼠评估 OPS-2071 和对照疗法的治疗效果。使用小鼠脾细胞和人外周血单核细胞评估 LPS 诱导的 TNF-α 产生的体外抑制作用和抗-CD3/CD28 抗体包被珠刺激的 T 细胞反应的抑制作用。此外，还测试了对与 IBD 发病机制相关的细菌的体外活性。
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。体外，OPS-2071 以剂量依赖性方式抑制 LPS 刺激诱导的 TNF-α 产生和 T 细胞反应。在高浓度下，这些作用在小鼠和人细胞中与现有免疫抑制剂（如泼尼松龙）相当。OPS-2071 还对与 IBD 相关的细菌表现出抗菌活性。
我们的结果表明，OPS-2071 具有免疫抑制和抗菌作用。这种双重作用使 OPS-2071 成为 IBD 的一种独特且有前途的候选药物。
