Targeting Inhibitory T cell Receptors for PcP Therapy

靶向抑制性 T 细胞受体进行 PcP 治疗

• 批准号: 8927877
• 负责人: Terry W Wright
• 金额: $ 23.03万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-16 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8927877
• 关键词: Acquired Immunodeficiency Syndrome; Address; Adopted; Antibiotic Resistance; Antibiotics; Antifungal Agents; Basic Science; CD4 Positive T Lymphocytes; CD8-Positive T-Lymphocytes; CD8B1 gene; Cell physiology; Cells; Cessation of life; Chronic; Clinic; Clinical; Data; Disease; Environment; Exploratory/Developmental Grant; Failure; Goals; Host Defense; Immune; Immune response; Immune system; Immunity; Immunosuppression; Immunosuppressive Agents; In Vitro; Infection; Inflammation; Inflammatory; Injury; Lead; Lung; Mediating; Medical; Mission; Molecular; Morbidity - disease rate; Mus; Organism; Outcome; Pathway interactions; Patient Care; 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; T-Lymphocyte Subsets; Therapeutic Intervention; Translating; Treatment Failure; United States National Institutes of Health; Ventilator; Viral Cancer; Virus Diseases; Work; cell type; cytokine; design; exhaust; exhaustion; fighting; functional restoration; improved; in vivo; interest; killings; mortality; 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. 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. In the absence of CD4 cells, the CD8+ T cell population recruited to the lungs lacks effector activity and may even suppress residual lung immunity allowing, Pc to grow and disease to progress. However, it has also been demonstrated that CD8+ T cells can be activated to eradicate PC infection in the absence CD4+ T cells. We have found that the majority of CD8+ T cells recruited to the lungs during PC infection express the inhibitory receptor PD-1, which is also a marker of T cell exhaustion. PD-1 signaling inhibits T effector function and is also important for Treg function. 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 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（由申请人提供）：肺孢子虫肺炎（PcP）仍然是免疫受损患者发病和死亡的重要原因。尽管可以采取有效的预防措施，但美国每年仍会发生 5,000-10,000 例病例，而全世界则有超过 400,000 例病例发生。 PCP 的死亡率为 10-20%，导致数千人死亡并导致严重发病。此外，需要呼吸机支持的患者死亡率高达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微生物。在这项探索性/开发资助中，我们建议确定抑制性 T 细胞受体的激活是否会限制 CD8+ T 细胞对抗 CD4 功能受损的宿主中 PC 感染的能力。在缺乏 CD4 细胞的情况下，招募到肺部的 CD8+ T 细胞群缺乏效应活性，甚至可能抑制残余的肺部免疫，从而导致 PC 生长和疾病进展。然而，也已证明，在缺乏 CD4+ T 细胞的情况下，CD8+ T 细胞可以被激活以根除 PC 感染。我们发现，在 PC 感染期间，大多数招募到肺部的 CD8+ T 细胞表达抑制性受体 PD-1，这也是 T 细胞耗竭的标志。 PD-1 信号传导抑制 T 效应子功能，对 Treg 功能也很重要。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传导，我们相信这些细胞可以被拯救并恢复效应器功能。这项探索性/开发资助的总体目标是确定 T 细胞抑制性受体是否限制 CD8+ T 细胞的抗 PC 效应器功能，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 PcP 期间抑制性受体表达是否定义了功能上不同的 CD8+ T 细胞亚群； 2) 确定抑制性受体阻断是否可以恢复 CD8+ T 细胞效应功能和抗 PC 宿主防御。拟议的研究将增强我们对宿主针对 PC 感染的防御的理解，并有可能产生新的治疗策略，这些策略可以转化为改善患者的症状 关心。