Novel Therapeutic Approaches For Treatment of Intestinal Inflammation

治疗肠道炎症的新方法

• 批准号: 9232271
• 负责人: Timothy L Denning
• 金额: $ 34.09万
• 依托单位: GEORGIA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-07-01 至 2021-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9232271
• 关键词: Acute; Adverse effects; Affect; Alginates; Anti-Tumor Necrosis Factor Therapy; Antigen-Presenting Cells; Biological Process; Cell Differentiation process; Cells; Chitosan; Chronic; Clinic; Colitis; Colon; Crohn' s disease; Data; Development; Disease; Dose; Encapsulated; Epithelial; Etiology; FOXP3 gene; Homing; Human; Hydrogels; In Vitro; Inflammation Mediators; Inflammatory; Inflammatory Bowel Diseases; Inflammatory disease of the intestine; Interleukin-12; Intestines; Malignant Neoplasms; Mediating; Modeling; Monoclonal Antibodies; Opportunistic Infections; Oral; Oral Administration; Pathogenesis; Patients; Pharmaceutical Preparations; Play; Production; Recombinants; Regimen; Regulatory T-Lymphocyte; Role; Severity of illness; Site; Small Interfering RNA; Symbiosis; TNF gene; Testing; Toxic effect; Ulcerative Colitis; United States; Wound Healing; adaptive immune response; cytokine; dosage; improved; in vivo; infliximab; innovation; interleukin-22; interleukin-23; macrophage; microbiota; mouse model; nanoparticle; novel; novel strategies; novel therapeutic intervention; repaired; targeted treatment

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.

总结 两种最常见的炎症性肠病（IBD），克罗恩病和溃疡性结肠炎， 影响美国约140万人。IBD的病因尚不清楚， 针对肠道微生物群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程度，并针对其中一些 因子已被证明在IBD患者的治疗中有效。特别是TNFα作为一种促凋亡因子发挥着至关重要的作用， 炎症介质在炎症性肠病的发病机制和抗TNF α单克隆抗体，英夫利西单抗，现在是 在临床上成功用于治疗人类IBD。然而，抗TNF α治疗仅对一部分人有效 IBD患者和关注仍然是关于不良反应，如癌症和机会性感染。的 观察到的不良反应主要是由于缺乏靶向治疗和通常被认为是“过量”的药物。 这是全身给药所固有的。最近，一种针对IL-12和IL-23的单克隆抗体， 乌司奴单抗对IBD患者有效，尤其是那些抗TNF α治疗 以前失败了。因此，人IBD的治疗可以通过允许治疗的新的递送方案来优化。 靶向低剂量抑制TNF-α和IL-12/23。我们已经证明， 负载TNFα siRNA并包封在藻酸盐-壳聚糖水凝胶中的纳米颗粒可以有效地 靶向结肠而无毒性，并减少小鼠模型中的肠道炎症。整理的丰厚 初步数据表明含有siRNA的纳米颗粒对肠抗原的特异性靶向 呈递细胞可以增强这种新的治疗方法的有益效果。在这些过程中， 研究中，我们还发现，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。这些发现使我们提出， 纳米颗粒介导的TNFα、IL-12/23和IL-22的操纵限制了肠道炎症， 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 而同时促进伤口愈合可有助于开发用于 人类IBD的治疗。