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: 8510507
• 负责人: Peter B. Ernst
• 金额: $ 19.38万
• 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 2015-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8510507
• 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）：世界上一半以上的人口感染幽门螺杆菌。众所周知，个体通常在儿童时期受到感染，并且感染持续终生。正是这种感染的持续性导致了一系列事件，导致胃炎、胃十二指肠溃疡、胃癌和淋巴瘤。幽门螺杆菌的流行病学研究未能确定一种能够可靠地预防感染的干预措施，特别是在穷人中。抗生素治疗仅推荐用于预防溃疡复发和作为早期胃恶性肿瘤感染患者的辅助治疗。迄今为止，疫苗接种尚未成功。因此，在缺乏有效的方法来预防或治疗这种持续性感染的情况下，需要新的干预策略来避免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）已被确定为促进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Treg含量增加。此外，减少Treg使局部宿主反应增强，感染减少。我们已经确定胞外腺苷，一种由Treg产生的介质，在维持幽门螺杆菌的持续感染中起主要作用。我们长期