Recombinant murine IL-10 produced in situ by H. pylori

描述（由申请人提供）：H。幽门螺杆菌被称为当今世界人类最常见的传染病。在世界范围内，50-100%的人感染H。幽门螺杆菌，但只有少数发展的临床症状的疾病。近20年的研究已经达成共识，即宿主免疫反应是决定感染结果的关键因素。由于H.幽门螺杆菌感染是一种辅助性T细胞-1介导的免疫应答，与高水平的IFN γ和低水平的IL-10及其它抗炎介质相关。 了解细胞因子在H. pylori具有诊断和治疗意义。首先，鉴定调节性细胞因子如IL-10或TGF β可能导致进一步理解调节途径和开发治疗那些患有难治性感染的个体的疗法。第二，也许同样重要的是，这种理解可以导致识别可能是应答者或非应答者的个人的能力。个体对H的反应差异很大。幽门螺杆菌，可能是因为不同的免疫反应性，每一个单独的主机。由于IL-10与H. pylori应答，我们选择将该初步研究集中在IL-10上。 我们的总体目标是检验H. pylori减轻或预防小鼠胃炎。这一目标将通过两个具体目标实现： 目标1：工程化H. pylori中表达重组鼠IL- 10。 目的2：确定在体内表达是否导致预防或解决胃炎对重组细菌或野生型H。与重组菌株共定殖的幽门螺杆菌。 简单地说，我们将构建重组H。表达鼠IL-10的幽门螺杆菌，证明细胞因子在培养物中和小鼠胃中由细菌表达，并确定这种表达是否改善或预防严重胃炎小鼠模型中的炎症。一个成功的结果将不仅决定IL-10在H.幽门螺杆菌，但也将建立一个模型，其中其他细胞因子和介质的作用可以确定，宿主和细菌的相互作用可以直接在体内评估。

DESCRIPTION (provided by applicant): H. pylori has been called the most common infectious disease of humans in the world today. Worldwide, between 50-100% of people are infected with H. pylori, but only a minority of those develop clinical signs of disease. Almost 2 decades of research have resulted in a general consensus that host immune response is a critical factor in determining the outcome of infection. Gastritis due to H. pylori is a T helper-1-mediated immune response associated with high levels of IFNgamma and low levels of IL-10 and other anti-inflammatory mediators. Understanding cytokine function in gastritis due to H. pylori has both diagnostic and therapeutic significance. First, identification of regulatory cytokines such as IL-10 or TGFbeta could lead to further understanding of regulatory pathways and development of therapies for those individuals with intractable infections. Second and perhaps equally important, such understanding could lead to the ability to identify individuals likely to be responders or non-responders. Individuals vary widely in their response to H. pylori, likely because of varying immunoreactivity of each individual host. Because of the strong association between IL-10 and immunoregulation of H. pylori responses, we have chosen to focus this pilot study on IL-10. Our overall goal is to test the hypothesis that recombinant murine IL-10 produced in situ by H. pylori ameliorates or prevents gastritis in mice. This goal will be accomplished in 2 specific aims: Aim 1: To engineer H. pylori to express recombinant murine IL- 10. Aim 2: To determine if in vivo expression leads to prevention or resolution of gastritis in response to recombinant bacteria or to wild-type H. pylori that co-colonize with recombinant strains. Briefly, we will construct recombinant H. pylori that expresses murine IL-10, demonstrate that the cytokine is expressed by bacteria in culture and in the mouse stomach, and determine if such expression ameliorates or prevents inflammation in a mouse model of severe gastritis. A successful outcome will not only determine the potential therapeutic role of IL-10 in gastritis due to H. pylori, but will also establish a model in which the roles of other cytokines and mediators can be determined, and host and bacterial interactions can be directly evaluated in vivo.