Mast Cells and IBD Pathogenesis

描述（由申请人提供）：目前认为，针对来自常驻肠道细菌的抗原的异常免疫反应有助于遗传易感宿主炎症性肠病（IBD）的发病机制。然而，所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一无二的，当受到刺激时，除了从头产生细胞因子外，它们还能释放预先储存的TNF。肠肥大细胞具有合适的受体，其物理位置可以对突破上皮屏障的肠道细菌迅速作出反应。我们和其他人已经证明，它们释放的TNF对于控制细菌感染和刺激抗原特异性免疫反应至关重要。因此，我们假设肥大细胞和肥大细胞衍生的TNF在IBD的诱导和延续中起关键作用。在这项研究中，肥大细胞缺陷的IL-10-/-小鼠将通过杂交现有的市售菌株创建。这些小鼠对结肠炎的易感性将在是否存在用过继转移的野生型或缺乏tnf的肥大细胞重建的情况下确定。肥大细胞刺激对结肠炎发展的影响将直接用肥大细胞充足的IL-10-/-小鼠来确定。最后，将开发抑制胃肠道肥大细胞活性的治疗方法。这些研究结果对人类IBD的预防和治疗具有直接意义。如果有指示，后续研究将旨在确定IBD中肥大细胞活性的机制，以及更严格的肥大细胞抑制剂治疗已建立的IBD的疗效研究。

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.