Novel Therapeutic Approaches For Treatment of Intestinal Inflammation

摘要 炎症性肠病(IBD)的两种最常见形式，克罗恩病和溃疡性结肠炎， 影响到美国大约140万人。IBD的病因尚不清楚，但先天异常 而针对共生微生物区系的适应性免疫反应被认为是疾病的基础 发病机制。许多促炎因子有助于疾病的严重性，并以其中一些为目标 因子已被证明对IBD患者的治疗有效。尤其是肿瘤坏死因子α发挥着至关重要的作用，因为它是 炎性介质在炎症性肠病发病机制中的作用及抗肿瘤坏死因子α的单抗英夫利昔单抗 已成功应用于临床治疗人类IBD。然而，抗肿瘤坏死因子α疗法仅在部分患者中有效。 IBD患者和对癌症和机会性感染等不良反应的担忧依然存在。这个 观察到的不良反应主要是由于缺乏有针对性的治疗和通常 全身性给药所固有的。最近，一种针对IL-12和IL-23的单抗， Ustekinumab被证明对炎症性肠病患者有效，特别是那些接受抗肿瘤坏死因子α治疗的患者 之前失败了。因此，人类IBD的治疗可以通过允许 靶向、低剂量抑制肿瘤坏死因子-α和白介素12/23。我们已经证明了口服给药 纳米粒负载肿瘤坏死因子αsiRNA，并包裹在海藻酸盐-壳聚糖水凝胶中，可以有效地 在小鼠模型中，靶向结肠无毒性，并减少肠道炎症。我们激动人心的 初步数据表明，含有siRNA的纳米颗粒对肠道抗原具有特异性靶向 提供细胞可能会增强这种新的治疗方法的有益效果。在这个过程中 研究还发现，抑制促炎细胞因子可能会产生意想不到的副作用 抑制关键的伤口愈合因子，如IL-22。这些发现促使我们提出 纳米粒介导的肿瘤坏死因子α、IL-12/23和IL-22抑制肠道炎症并促进 IBD期间伤口愈合。这些新策略旨在局部抑制关键的促炎细胞因子 同时促进伤口愈合可能有助于开发更好的治疗方法 人类IBD的治疗。

Summary The two most common forms of inflammatory bowel disease (IBD), Crohn's disease and ulcerative colitis, affect approximately 1.4 million people in the United States. The etiology of IBD is unclear, yet aberrant innate and adaptive immune responses directed towards the commensal microbiota are believed to underlie disease pathogenesis. Numerous pro-inflammatory factors contribute to disease severity and targeting some of these factors has proven effective in the treatment of IBD patients. TNFα in particular plays a crucial role as a pro- inflammatory mediator in the pathogenesis of IBD and the anti-TNFα monoclonal antibody, infliximab, is now successfully used in the clinic to treat human IBD. However, anti-TNFα therapy is only effective in a subset of IBD patients and concerns remain regarding adverse effects, such as cancer and opportunistic infections. The observed adverse effects are mainly due to the lack of targeted treatment and the “over dosage” that is usually inherent to systemic drug administration. More recently, a monoclonal antibody targeting IL-12 and IL-23, ustekinumab, was shown to be effective in IBD patients, especially those in which anti-TNFα therapy had previously failed. Thus, treatment of human IBD may be optimized by novel delivery regimens that allow for targeted, low-dose inhibition of both TNF-α and IL-12/23. We have demonstrated that oral administration of nanoparticles loaded with TNFα siRNA and encapsulated in an alginate-chitosan hydrogel can be efficiently targeted to the colon without toxicity and reduce intestinal inflammation in a mouse model. Our exciting preliminary data demonstrate that specific targeting of nanoparticles containing siRNA to intestinal antigen presenting cells may enhance the beneficial effects of this novel therapeutic approach. In the course of these studies, we also discovered that inhibition of pro-inflammatory cytokines can have the unexpected side effect of inhibiting critical wound-healing factors, such as IL-22. These finding have led us to propose that nanoparticle-mediated manipulation of TNFα, IL-12/23 and IL-22 limits intestinal inflammation and promotes wound healing during IBD. These novel strategies aimed at locally inhibiting key pro-inflammatory cytokines while simultaneously promoting wound healing may contribute to the development of improved therapies for the treatment of human IBD.