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）：超过一半的世界人口感染幽门螺杆菌。众所周知，个体通常在儿童时期感染，并且感染持续终生。正是这种感染的持续性导致了引起胃炎、胃十二指肠溃疡、胃癌和淋巴瘤的一系列事件。对H.幽门螺杆菌感染的研究未能确定一种有效预防感染的干预措施，特别是穷人。抗生素治疗仅推荐用于预防复发性溃疡和作为早期胃麦芽瘤感染患者的预防性治疗。到目前为止，疫苗还没有研制成功。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诱导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。在感染H. pylori感染，Treg在人和鼠胃组织中增加。此外，减少Treg允许局部宿主应答增强并且感染减少。我们已经确定，细胞外腺苷，调节性T细胞产生的介质，在维持持续感染H。幽门。 我们漫长 长期目标是开发一种治疗策略，以方便和安全地提高宿主免疫力，以清除感染。拟议研究的基本原理是，有利于持续感染的机制的新知识将暴露出可以进行干预的目标点。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，有利于清除持久的H。幽门感染拟议研究的广泛目标是评估阻断腺苷产生或作用于H。幽门螺杆菌感染，并测试一系列化合物预防这种生物体持续感染的能力。该目标将在以下具体目标中阐述：目标1：评价阻断腺苷产生/作用对持续性H的影响。幽门感染目的2：优化腺苷阻断剂增强抗菌免疫的效果。目的3：支持使用人体组织和非人灵长类动物进行药物开发的基本原理。总之，这些研究将促进靶向Treg功能介体的治疗方法的发展，这些介体减弱宿主反应并有利于H.幽门。这一新的信息将产生重要的积极影响，通过推进我们对持续性调节机制的理解，并作为新的治疗策略的基础，增强宿主对清除这些感染的反应。