H. PYLORI-SPECIFIC REGULATORY T CELLS THAT LIMIT HOST RESPONSE

描述(申请人提供)：幽门螺杆菌(H.Pylori)定植于人的胃粘膜，在胃炎和消化性溃疡疾病的发展中起病因学作用。尽管会诱发组织性胃炎和特异性免疫反应，但感染仍会持续终生。在幽门螺杆菌感染的小鼠模型中也观察到了类似的现象。然而，缺乏IL-10或NADPH氧化酶的小鼠对幽门螺杆菌的反应明显比受感染的野生型小鼠更强烈，并自发地将细菌从胃粘膜中清除出去。此外，免疫小鼠在攻击后根除幽门螺杆菌的同时也伴随着更强烈的炎症。因此，幽门螺杆菌可能会持续存在，因为宿主在感染过程中无法发展出足够强烈的炎症。已经描述了诱导下调T细胞以防止对结肠中非侵袭性细菌的异常反应。这些机制可能在胃肠道中是保守的，在胃粘膜中可能是活跃的。这项提议将检验这样一个假设，即幽门螺杆菌感染期间胃粘膜T细胞的激活诱导IL-10产生调节性T细胞，从而抑制炎症反应，从而允许持续感染。与这一假设相关的是，疫苗接种通过激活淋巴组织中的T细胞有效地绕过了这种下调，而淋巴组织中的T细胞不利于诱导产生IL-10的T细胞。我们将通过以下方式解决这一假设：1)表征感染和免疫小鼠胃T细胞的表面标志和细胞因子谱，以区分调节性和保护性T细胞。流式细胞术和ELISA斑点分析将用于检测新鲜分离的T细胞。2)确定胃粘膜中对这些调节细胞的诱导起作用的因素。转基因小鼠和共培养模型将被用来探索特定的辅助受体和细胞因子与胃中T细胞激活的关系。3)研究调节性T细胞如何与其他细胞相互作用以下调炎症。调节性T细胞将在小鼠体内和体外进行研究，以确定其调节特性的程度。这些研究将增加我们对胃肠道免疫调节的理解，并设计更好的免疫疗法。

DESCRIPTION (provided by applicant): Helicobacter pylori (H. pylori) colonizes the human gastric mucosa and plays an etiologic role in the development of gastritis and peptic ulcer disease. Infection persists for life despite the induction of histologic gastritis and specific immune responses. Similar observations have been made in the H. pylori-mouse model. However, mice lacking either IL-10 or NADPH oxidase develop inflammation in response to H. pylori that is significantly more intense than infected wild type mice, and spontaneously clear the bacteria from the gastric mucosa. Additionally, eradication of H. pylori from immunized mice following challenge is also accompanied by more intense inflammation. Therefore, H. pylori may persist due to the inability of the host to develop sufficiently intense inflammation during infection. The induction of down-regulatory T-cells that prevent aberrant responses to noninvasive bacteria in the colon has been described. These mechanisms may be conserved along the gastrointestinal tract and may be active in the gastric mucosa. This proposal will test the hypothesis that activation of T-cells at the gastric mucosa during H. pylori infection induces IL-10 producing regulatory T cells that suppress the inflammatory response, thus allowing for persistent infection. A correlate of this hypothesis is that vaccination effectively bypasses this down-regulation by activating T-cells in lymphoid tissue where the induction of IL-10 producing T-cells is not favored. We will address this hypothesis by: 1) Characterizing surface markers and cytokine profiles of gastric T cell from infected and immune mice to distinguish regulatory T-cells from protective T-cells. Flow cytometry and ELISA spot assays will be used to examine freshly isolated T-cells. 2) Identify the factors in the gastric mucosa that contribute to the induction of these regulatory cells. Transgenic mice and co-culture models will be used to explore the relationship of specific co-receptors and cytokines to T-cell activation in the stomach. 3) Investigate how regulatory T-cells interact with other cells to down-regulate inflammation. Regulatory T-cells will be studied in mice and in vitro to define the extent of their regulatory properties. These studies will increase our understanding of gastrointestinal immunoregulation and the design of better immunotherapies.