Inhibition of Treg function to cure persistent H. pylori infection

抑制Treg功能治疗持续性幽门螺杆菌感染

• 批准号: 8629690
• 负责人: Peter B. Ernst
• 金额: $ 20.55万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-03-04 至 2016-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8629690
• 关键词: Address; Adenosine; Advanced Development; Age; Anti-Bacterial Agents; Antibiotic Therapy; Antigens; Attenuated; Bacteria; Basic Science; Biological Assay; Biopsy Specimen; Cancer Etiology; Cells; Cessation of life; Childhood; Chronic; Clinical; Data; Development; Disease; Epidemiologic Studies; Event; Family; Gastric Tissue; Gastric lymphoma; Gastric mucosa; Gastritis; Goals; Helicobacter; Helicobacter Infections; Helicobacter pylori; Human; Immune response; Immunity; Individual; Infection; Infection prevention; Inflammation; Intervention; Knowledge; Lead; Leukocytes; Life; Macaca mulatta; Maintenance; Mediating; Mediator of activation protein; Molecular; Mus; Oral; Organism; Outcome; Patients; Phase; Play; Population; Prevention; Production; Purinergic P1 Receptors; Recurrence; Regulatory T-Lymphocyte; Research; Role; Severities; Staging; Stomach; Testing; Therapeutic; Ulcer; Vaccination; Vaccines; Work; age effect; base; design; drug development; epidemiology study; extracellular; human tissue; immunogenicity; malignant stomach neoplasm; nonhuman primate; novel; novel therapeutics; pathogen; prevent; public health relevance; receptor; response; translational approach

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.

描述（由申请人提供）：全世界一半以上的人口感染了幽门螺杆菌。众所周知，个人通常会在童年中感染，并且感染持续生命。正是这种感染的持续性导致导致胃炎，胃溃疡，胃癌和淋巴瘤的事件序列。幽门螺杆菌流行病学的研究未能确定一种可以可靠地感染的干预措施，尤其是穷人。仅建议对预防复发性溃疡进行抗生素治疗，并作为感染早期胃麦芽瘤患者的辅助治疗。迄今为止，尚未成功开发疫苗接种。因此，在没有有效的方法来预防或治愈这种持续感染的情况下，需要采取新颖的介入策略来避免这种持续感染引起的慢性炎症的临床后果。 调节性T细胞（Treg）已被确定为有利于持续感染的重要因素。在幽门螺杆菌感染期间，人和鼠胃组织中的Treg增加。此外，depulting treg允许局部宿主对加强的反应，并减少感染。我们已经确定，由Treg产生的介体细胞外腺苷在维持对幽门螺杆菌的持续感染中起着重要作用。 我们的漫长 术语目标是制定一种治疗策略，以轻松安全地安全增强宿主的免疫力清除感染。拟议研究的理由是，对有利于持续感染的机制的新知识将暴露出可以针对干预的点。这导致了我们目前的假设，即阻止腺苷的作用将增强免疫力并有利于清除幽门螺杆菌感染。拟议研究的广泛目标是评估阻断腺苷产生或作用对幽门螺杆菌感染的作用的影响，并测试化合物家族的能力，以防止这种生物体持续感染。该目标将在以下特定目的中解决：目标1：评估阻断腺苷产量/作用对幽默幽门螺杆菌感染的影响。目标2：优化阻断腺苷以增强抗细菌免疫的功效。 AIM 3：支持使用人组织和非人类灵长类动物的药物开发基本原理。总之，这些研究将推进针对Treg功能介体的治疗方法的发展，这些方法可以减轻宿主反应并促进幽门螺杆菌的持续感染。这些新信息将通过促进我们对调节持久性的机制的理解，并作为新的治疗策略的基础，从而增强宿主对清除这些感染的反应，从而产生重要的积极影响。