Targeting Inhibitory T cell Receptors for PcP Therapy

靶向抑制性 T 细胞受体进行 PcP 治疗

基本信息

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
项目类别：
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

项目摘要

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（由适用提供）：肺炎囊肿（PCP）仍然是免疫受损患者发病率和发病率的重要原因。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，需要通风呼吸机支持的患者的死亡率为50％甚至更高。因此，在没有感染和伤害的情况下，确定需要新的治疗策略，可以迅速实现组织。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细胞在CD4功能受损的宿主中对抗PC感染的能力。在没有CD4细胞的情况下，募集到肺部的CD8+ T细胞群缺乏效应子活性，甚至可能抑制残留的肺免疫，使PC生长和疾病进展。但是，还证明，在没有CD4+ T细胞的情况下，CD8+ T细胞可以激活以辐射PC感染。我们发现，在PC感染期间，大多数CD8+ T细胞募集到肺部表达抑制性受体PD-1，这也是T细胞耗尽的标志。 PD-1信号传导抑制T效应功能，对Treg功能也很重要。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。通过阻止抑制性受体信号传导，我们认为这些细胞可以恢复并恢复效应子功能。该探索性 /发育授权的总体目标是确定T细胞抑制受体是否限制CD8+ T细胞的抗PC效应功能，并在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，以改善患者关心。