Inhibition of Treg function to cure persistent H. pylori infection

描述(申请人提供)：世界上超过一半的人口感染幽门螺杆菌。众所周知，个人通常在童年时感染，并持续终生。正是这种感染的持续性导致了一系列导致胃炎、胃十二指肠溃疡、胃癌和淋巴瘤的事件。对幽门螺杆菌流行病学的研究未能找到可靠地预防感染的干预措施，特别是对穷人。抗生素治疗只被推荐用于预防复发的溃疡，并作为早期胃粘膜瘤感染患者的辅助治疗。到目前为止，疫苗接种尚未成功开展。因此，在缺乏预防或治愈这种持续性感染的有效方法的情况下，需要新的干预策略来避免由这种持续性感染引起的慢性炎症的临床后果。调节性T细胞(Treg)已被确认为有利于持续感染的重要因素。在幽门螺杆菌感染过程中，人和小鼠胃组织中Treg的表达增加。此外，减少Treg的种群可以增强当地宿主的反应，减少感染。我们已经发现，Treg产生的细胞外腺苷在维持幽门螺杆菌的持续感染中起着重要作用。我们的龙 长期目标是开发一种治疗策略，轻松安全地提高宿主免疫力，以清除感染。这项拟议研究的基本原理是，对有利于持续感染的机制的新知识将暴露出可以作为干预目标的点。这导致了我们目前的假设，即阻断腺苷的作用将增强免疫力，并有利于清除持续的幽门螺杆菌感染。拟议研究的主要目标是评估阻断腺苷产生或作用对幽门螺杆菌感染的影响，并测试一系列化合物预防这种生物持续感染的能力。目标1：评价阻断腺苷产生/作用对幽门螺杆菌持续感染的影响。目的2：优化腺苷封闭剂的药效，提高抗菌免疫能力。目的3：支持使用人类组织和非人类灵长类动物进行药物开发的理论基础。总之，这些研究将推动针对Treg功能介体的治疗方法的开发，这些介体可以减弱宿主的反应，并有利于持续感染幽门螺杆菌。这一新信息将通过促进我们对调节持久性的机制的理解而产生重要的积极影响，并作为增强宿主反应以清除这些感染的新治疗策略的基础。

DESCRIPTION (provided by applicant): Over half of the world's population is infected with Helicobacter pylori. It is well known that individuals usually get infected in childhood and the infection persists for life. It is the persistence of this infection that leads to the sequence of events that cause gastritis, gastroduodenal ulceration, gastric cancer and lymphoma. Studies of the epidemiology of H. pylori have failed to identify an intervention that would prevent infection reliably, particularly of the poor. Antibiotic treatment is only recommended for the prevention of recurrent ulcers and as an adjunctive therapy for infected patients with early stage gastric maltomas. To date, vaccination has not been developed successfully. Thus, in the absence of effective approaches to prevent or cure this persistent infection, novel interventional strategies are required to avoid the clinical consequences of chronic inflammation induced by this persistent infection. Regulatory T cells (Treg) have been identified as important factors in favoring persistent infection. During infection with H. pylori, Treg are increased in human and murine gastric tissue. Further, depopulating Treg allows the local host responses to intensify and infection is decreased. We have identified that extracellular adenosine, a mediator produced by Treg, plays a major role in sustaining the persistent infection to H. pylori. Our long term goal is to develop a therapeutic strategy to easily and safely boost host immunity to clear infection. The rationale for the proposed research is that new knowledge of the mechanisms that favor persistent infection will expose points that can be targeted for intervention. This lead to our current hypothesis that blocking the action of adenosine will enhance immunity and favor the clearance of persistent H. pylori infection. The broad objectives for the proposed studies are to evaluate the effects of blocking adenosine production or action on H. pylori infection and test a family of compounds for their ability to prevent persistent infection with this organism. This objective will be addressed in the following Specific Aims: Aim 1: Evaluate the effect of blocking adenosine production/action on persistent H. pylori infection. Aim 2: Optimize the efficacy of blocking adenosine to enhance anti-bacterial immunity. Aim 3: Support the rationale for drug development using human tissue and non-human primates. Together, these studies will advance the development of therapeutic approaches targeting mediators of Treg function that attenuate host responses and favor persistent infection with H. pylori. This new information will have an important positive impact by advancing our understanding of the mechanisms regulating persistence and serve as the basis for new therapeutic strategies that enhance host responses to clear these infections.