Reversing inhibitory receptor signaling for PcP Therapy

逆转 PcP 疗法的抑制性受体信号传导

基本信息

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
项目类别：
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

项目摘要

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（由申请人提供）：肺孢子菌肺炎 (PCP) 仍然是免疫受损患者（尤其是 HIV/AIDS 患者）发病和死亡的重要原因。根据 CDC，住院 AIDS 患者中 PCP 的发病率约为 9%。尽管有有效的预防措施，美国每年仍会发生 5,000-10,000 例死亡病例，而全球则有超过 400,000 例死亡。 PCP 导致数千人死亡，发病率高达 10-20%。此外，需要呼吸机支持的患者死亡率高达 50% 甚至更高，因此，迫切需要快速的新型治疗策略。在没有炎症和损伤的情况下根除生物体在这项探索性/开发资助中，我们建议确定抑制性 T 细胞受体的激活是否限制 CD8+ T 的能力。尽管已证明某些 CD8+ T 细胞亚群可以提供抗 PC 宿主防御，但在 CD4 缺陷宿主中招募到肺部的 CD8+ T 细胞群缺乏宿主防御功能，因此无法在 CD4 功能受损的宿主中对抗 PC 感染。甚至可能抑制残余的肺部免疫力，从而导致 PC 生长和疾病进展。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 和 LAG-3，它们是 T 的标志物。细胞PD-1 和 LAG-3 信号传导抑制 T 效应子功能，并且对于 Treg 介导的抑制也很重要，因此，我们发现慢性 PC 感染的肺中的 CD8 细胞采用衰竭和/或抑制表型。限制这些细胞的宿主防御功能，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利用 HIV 相关 PcP 的小鼠模型来实现。确定 T 细胞抑制性受体是否限制 CD8+ T 细胞的抗 PC 效应功能，并导致 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) 确定是否。抑制性受体表达定义了 PcP 期间功能不同的 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。了解宿主对 PC 感染的防御，并有可能产生新的治疗策略，从而改善患者护理。