Reversing inhibitory receptor signaling for PcP Therapy

逆转 PcP 疗法的抑制性受体信号传导

• 批准号: 9243968
• 负责人: Terry W Wright
• 金额: $ 7.69万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-03-15 至 2019-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9243968
• 关键词: AIDS/HIV problem; Acquired Immunodeficiency Syndrome; Address; Adopted; Alveolar; Alveolar Macrophages; Antibiotic Resistance; Antibiotics; Antifungal Agents; Basic Science; Biological Response Modifiers; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CD8B1 gene; Cell physiology; Cells; Centers for Disease Control and Prevention (U.S.); Cessation of life; Chronic; Clinic; Clinical; Data; Data Science; Disease; Effector Cell; Environment; Environmental air flow; Epithelial Cells; Exploratory/Developmental Grant; Failure; Goals; HIV; Host Defense; Immune; Immune response; Immune system; Immunity; Immunosuppression; Immunosuppressive Agents; Impairment; In Vitro; Incidence; Infection; Inflammation; Inflammatory; Injury; Lead; Ligands; Lung; Mediating; Medical; Mission; Molecular; Morbidity - disease rate; Mus; Organism; Pathway interactions; Patient Care; Patient-Focused Outcomes; Patients; Phenotype; Pneumocystis carinii Pneumonia; Population; Primates; Prophylactic treatment; Rattus; Receptor Signaling; Recruitment Activity; Regimen; Regulatory T-Lymphocyte; Research; Research Design; Residual state; Respiratory physiology; SIV; Signal Transduction; T-Cell Receptor; T-Lymphocyte; Therapeutic Intervention; Translating; Treatment Failure; United States National Institutes of Health; Ventilator; Viral Cancer; Virus Diseases; cell type; cytokine; design; exhaust; exhaustion; fighting; functional restoration; improved; in vivo; interest; killings; mortality; mouse model; novel; novel therapeutics; pathogen; public health relevance; receptor; receptor expression; response; translational study

 DESCRIPTION (provided by applicant): Pneumocystis pneumonia (PCP) remains an important cause of morbidity and mortality among immune compromised patients, especially those with HIV/AIDS. According to the CDC, the incidence of PCP is approximately 9% among hospitalized AIDS patients. Despite the availability of effective prophylaxis, each year 5,000-10,000 cases occur in the U.S. and more than 400,000 cases occur worldwide. With a mortality rate of 10-20% there are thousands of deaths and significant morbidity as a result of PCP. Furthermore, patients requiring ventilator support have a mortality rate of 50% or even higher. Therefore, there is a definite need for novel therapeutic strategies that quickly eradicate the organism in the absence of inflammation and injury. In this exploratory/developmental grant, we propose to determine whether activation of inhibitory T cell receptors limits the ability of CD8+ T cells to fight PC infection in hosts with impaired CD4 function. Although it has been demonstrated that certain CD8+ T cell subsets can provide anti-PC host defense, the CD8+ T cell population recruited to the lungs in CD4-deficient hosts lacks host defense function and may even suppress residual lung immunity, allowing PC to grow and disease to progress. We have found that the majority of CD8+ T cells recruited to the lungs during PC infection express the inhibitory receptors PD-1 and LAG-3, which are markers of T cell exhaustion. PD-1 and LAG-3 signaling inhibit T effector function and are also important for Treg- mediated suppression. Thus, we hypothesize that CD8 cells in the lungs of chronically PC-infected lungs adopt an exhausted and/or suppressor phenotype, which limits the host defense function of these cells. By blocking inhibitory receptor signaling we believe that these cells can be rescued and effector function restored. The overall goal of this exploratory/developmental grant is utilize a mouse model of HIV-related PcP to determine whether T cell inhibitory receptors limit the anti-PC effector function of CD8+ T cells and contribute to an immunosuppressive lung environment in hosts with impaired CD4+ T cell function. To accomplish this goal we will complete the following Specific Aims: 1) To determine whether inhibitory receptor expression defines functionally distinct CD8+ T cell subsets during PcP; 2) To determine whether inhibitory receptor blockade restores CD8+ T cell effector function and anti-PC host defense. The proposed research will enhance our understanding of host defense against PC infection, and has the potential to lead to novel therapeutic strategies that can be translated to improve patient care.

 描述(申请人提供)：肺孢子虫肺炎(PCP)仍然是免疫功能低下的患者，特别是艾滋病毒/艾滋病患者发病和死亡的重要原因。根据美国疾病控制与预防中心的数据，在住院的艾滋病患者中，PCP的发病率约为9%。尽管有有效的预防措施，但美国每年都会发生5000-10000个病例，全世界都有超过40万个病例。PCP的死亡率为10%-20%，有数千人死亡，发病率很高。此外，需要呼吸机支持的患者的死亡率为50%甚至更高。因此，确实需要新的治疗策略，在没有炎症和损伤的情况下快速根除有机体。在这项探索性/发展性授权中，我们建议确定抑制性T细胞受体的激活是否限制了CD8+T细胞的能力 在CD4功能受损的宿主中对抗PC感染的细胞。虽然已经证明某些CD8+T细胞亚群可以提供抗PC宿主防御，但在CD4缺乏的宿主中，CD8+T细胞群招募到肺部的CD8+T细胞群缺乏宿主防御功能，甚至可能抑制残留的肺免疫，使PC生长和疾病进展。我们发现，在PC感染期间，大多数CD8+T细胞被招募到肺部，表达抑制受体PD-1和LAG-3，这是T细胞耗竭的标志。PD-1和LAG-3信号通路抑制T效应分子的功能，对Treg介导的抑制也很重要。因此，我们假设慢性PC感染肺中的CD8细胞采用耗尽和/或抑制表型，这限制了这些细胞的宿主防御功能。通过阻断抑制性受体信号，我们相信可以挽救这些细胞，恢复效应器功能。这项探索性/发展性赠款的总体目标是利用HIV相关PCP的小鼠模型来确定T细胞抑制受体是否限制了CD8+T细胞的抗PC效应功能，并有助于CD4+T细胞功能受损的宿主的免疫抑制肺环境。为了实现这一目标，我们将完成以下具体目标：1)确定在PCP过程中抑制性受体的表达是否定义了不同的CD8+T细胞亚群；2)确定抑制性受体阻断是否恢复了CD8+T细胞的效应功能和抗PC宿主防御。这项拟议的研究将增强我们对宿主防御PC感染的理解，并有可能导致新的治疗策略，这些策略可以转化为改善患者护理。