Mast Cells and IBD Pathogenesis

肥大细胞和 IBD 发病机制

• 批准号: 7128496
• 负责人: Laura P. Hale
• 金额: $ 23.33万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-01 至 2008-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7128496
• 关键词: bacteria infection mechanism; cell population study; colitis; enteric bacteria; gastrointestinal epithelium; genetically modified animals; host organism interaction; inflammatory bowel diseases; intestinal mucosa; laboratory mouse; mast cell; mucosal immunity; pathologic process; tumor necrosis factor alpha

DESCRIPTION (provided by applicant): Aberrant immune responses against antigens derived from resident intestinal bacteria are currently believed to contribute to the pathogenesis of inflammatory bowel disease (IBD) in a genetically susceptible host. However, the cell types involved and the specific mechanisms that result in the development of IBD remain poorly defined. Mast cells are well-known contributors to pathogenesis of immune-mediated diseases such as allergy and asthma. They are unique among inflammatory cells in their ability to release pre-stored TNF when stimulated in addition to de novo cytokine production. Intestinal mast cells bear appropriate receptors and are physically located where they can rapidly respond to enteric bacteria that breach the epithelial barrier. We and others have shown that the TNF they release is critical for control of bacterial infections and for stimulation of antigen-specific immune responses. Thus we hypothesize that mast cells and mast cell-derived TNF play a critical role in the induction and perpetuation of IBD. In this study, mast cell-deficient IL-10-/- mice will be created by cross-breeding existing commercially available strains. The susceptibility of these mice to development of colitis will be determined in the presence and absence of reconstitution with adoptively transferred wild type or TNF-deficient mast cells. The effect of mast cell stimulation on development of colitis will be determined directly using mast cell-sufficient IL-10-/- mice. Finally, treatments that inhibit mast cell activity in the gastrointestinal tract will be developed. The results of these studies have direct implications for both prevention and treatment of IBD in humans. If indicated, follow-up studies will be aimed at determining the mechanisms underlying mast cell activity in IBD as well as more rigorous studies of the efficacy of mast cell inhibitors for therapy of established IBD.

描述（由申请方提供）：目前认为，针对源自常驻肠道细菌的抗原的异常免疫应答有助于遗传易感宿主中炎症性肠病（IBD）的发病机制。然而，涉及的细胞类型和导致IBD发展的具体机制仍然不清楚。肥大细胞是众所周知的免疫介导的疾病，如过敏和哮喘的发病机制的贡献者。它们在炎症细胞中是独特的，除了从头产生细胞因子外，当受到刺激时，它们还能够释放预先储存的TNF。肠肥大细胞具有适当的受体，并且在物理上位于它们可以对破坏上皮屏障的肠细菌快速响应的位置。我们和其他人已经表明，它们释放的TNF对于控制细菌感染和刺激抗原特异性免疫应答至关重要。因此，我们推测肥大细胞和肥大细胞衍生的TNF在IBD的诱导和持续中起关键作用。在这项研究中，肥大细胞缺陷型IL-10-/-小鼠将通过杂交育种现有的市售菌株。将在存在和不存在过继转移的野生型或TNF缺陷型肥大细胞重建的情况下确定这些小鼠对结肠炎发展的易感性。将使用肥大细胞充足的IL-10-/-小鼠直接确定肥大细胞刺激对结肠炎发展的影响。最后，将开发抑制胃肠道中肥大细胞活性的治疗方法。这些研究的结果对人类IBD的预防和治疗有直接影响。如有指征，后续研究将旨在确定IBD中肥大细胞活性的潜在机制，以及对肥大细胞抑制剂治疗已确诊IBD的疗效进行更严格的研究。