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（由适用提供）：肺炎藻（PCP）仍然是免疫损害患者（尤其是患有HIV/艾滋病的患者）发病率和死亡率的重要原因。根据疾病预防控制中心，住院艾滋病患者的PCP事件约为9％。尽管有效预防有效，但每年在美国发生5,000-10,000例案件，全球有40万例案件发生。由于PCP，死亡率为10-20％，有数千人死亡和显着的发病率。此外，需要呼吸机支持的患者的死亡率为50％甚至更高。因此，在没有感染和损伤的情况下，肯定需要新的热策略来迅速实现生物体。在此探索性/发育授权中，我们建议确定抑制性T细胞受体的激活是否限制了CD8+ T的能力尽管已经证明某些CD8+ T细胞子集可以提供抗PC宿主防御，但CD8+ T细胞群体在CD4缺陷宿主中募集到肺部的CD8+ T细胞群缺乏宿主防御功能，甚至可能抑制残留的肺部免疫疗法，从而使PC生长并疾病进展。我们发现，在PC感染表达期间，大多数CD8+ T细胞募集到肺部抑制受体PD-1和LAG-3，它们是T细胞耗尽的标志物。 PD-1和LAG-3信号传导抑制T效应函数，对于Treg介导的抑制也很重要。这就是我们假设，慢性PC感染肺肺中的CD8细胞采用耗尽的和/或抑制剂表型，从而限制了这些细胞的宿主防御功能。通过阻断抑制受体，我们认为可以挽救这些细胞并恢复效应子功能。该探索性/发育赠款的总体目标是利用与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，并在患有受损CD4+ T细胞功能受损的宿主中有助于免疫抑制肺部环境。为了实现此目标，我们将完成以下特定目的：1）确定抑制受体表达是否定义了PCP期间功能上不同的CD8+ T细胞子集； 2）确定抑制受体阻滞是否恢复CD8+ T细胞效应子功能和抗PC宿主防御。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，以改善患者护理。