Reversing inhibitory receptor signaling for PcP Therapy

 描述（由申请方提供）：肺孢子虫肺炎（PCP）仍然是免疫功能低下患者，特别是HIV/AIDS患者发病和死亡的重要原因。根据CDC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，但美国每年仍有5，000 - 10，000例病例，全世界有40多万例病例。五氯苯酚的死亡率为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，确实需要在没有炎症和损伤的情况下快速根除生物体的新治疗策略。在这项探索性/发展性资助中，我们建议确定抑制性T细胞受体的激活是否限制了CD 8 + T细胞的能力。 细胞在CD 4功能受损的宿主中对抗PC感染。虽然已经证明某些CD 8 + T细胞亚群可以提供抗PC宿主防御，但在CD 4缺陷型宿主中招募到肺部的CD 8 + T细胞群体缺乏宿主防御功能，甚至可能抑制残留的肺部免疫，从而使PC生长和疾病进展。我们已经发现，在PC感染期间募集到肺部的大多数CD 8 + T细胞表达抑制性受体PD-1和LAG-3，这是T细胞耗竭的标志物。PD-1和LAG-3信号传导抑制T效应子功能，并且对于Treg介导的抑制也是重要的。因此，我们假设慢性PC感染的肺中的CD 8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功能。这项探索性/开发性资助的总体目标是利用HIV相关PcP的小鼠模型来确定T细胞抑制性受体是否限制CD 8 + T细胞的抗PC效应子功能，并有助于CD 4 + T细胞功能受损的宿主的免疫抑制性肺环境。为了实现这一目标，我们将完成以下具体目标：1）确定抑制性受体表达是否在PcP期间定义功能上不同的CD 8 + T细胞亚群; 2）确定抑制性受体阻断是否恢复CD 8 + T细胞效应子功能和抗PC宿主防御。拟议的研究将提高我们对PC感染的宿主防御的理解，并有可能导致新的治疗策略，可以转化为改善患者护理。

 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.