Role of PD1 blockade and IL-10 during infection in aging

PD1 阻断和 IL-10 在衰老感染过程中的作用

基本信息

批准号：
10509657
负责人：
Christina Camell
金额：
$ 22.61万
依托单位：
UNIVERSITY OF MINNESOTA
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-15 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10509657
关键词：
2019-nCoV Address Adoptive Transfer Affect Age Aging Anti-Inflammatory Agents Antigens CD8-Positive T-Lymphocytes COVID-19 pandemic Cause of Death Cell model Cell physiology Cells Cellular Indexing of Transcriptomes and Epitopes by Sequencing Chronic Chronic Disease Combined Modality Therapy Complement Data Elderly Exposure to Foundations Future Gene Expression Profile Genes Goals Hospital Mortality Hospitalization Human Immune Immune system Immunotherapy In Vitro Individual Infection Infection Control Inflammaging Influenza Interleukin-10 Knock-out Lymphocyte Lymphocyte Subset Measures Microbe Morbidity - disease rate Mus PD-1 blockade PI3 gene Pathology Pathway interactions Patients Play Pneumonia Proto-Oncogene Proteins c-akt Receptor Activation Receptor Signaling Recombinants Risk Role STAT3 gene Sepsis Signal Pathway Signal Transduction Source Stains T memory cell T-Cell Activation T-Cell Receptor T-Lymphocyte Testing Therapeutic Uses Tissues Transcriptional Activation Translations Tumor-infiltrating immune cells Virus Work aged base cancer immunotherapy cell type chronic infection co-infection cytokine cytokine release syndrome cytotoxic differential expression effector T cell exhaust exhaustion experience high risk immunosenescence improved improved outcome infectious disease treatment influenza pneumonia microbial mortality mortality risk mouse model novel strategies novel therapeutics prevent programmed cell death protein 1 protective effect response seasonal influenza secondary infection severe COVID-19 young adult

项目摘要

PROJECT SUMMARY The elderly are at high risk for mortality to infection, with influenza and pneumonia consistently ranked among the top leading causes of death in the US for those over 65. There is also an increased rate of co-infections in the elderly admitted to the ICU that is associated with hospital mortality. There is a need for novel approaches that rejuvenate the aged immune system to promote the control of infection. We leverage an experimental paradigm that exposes experimental mice to multiple microbes (termed normal microbial experience; NME). NME activates the immune system in young mice, increasing functional memory T cells. However, in old mice, NME-exposure leads to 100% mortality that is preceded by a cytokine storm and increased immune infiltrates in multiple tissues. Existing evidence demonstrates that immunosenescence, including inflammaging and the dysfunctional immune system, play a causal role in morbidity to infections in the elderly. Exhaustion is a cell fate that is increased in lymphocytes from the elderly, and which contributes to inflammaging, virus persistence, and tissue pathology. It is primarily enforced by chronic antigen exposure, but also regulated by local secreted factors, like IL-10 in younger individuals. It is unknown how specific factors control exhaustion prior to and during infection in older individuals. We speculate that IL-10, a traditional anti-inflammatory cytokine that accumulates with age, and which also has pro-cytotoxic effects on CD8 T cells, is a regulator of exhaustion with age. This proposal is based on our exciting preliminary data which describes the effect of PD1 blockade, which reduces exhaustion by restoring T cell activation and implicates IL-10 in that response. Based on our data, we wonder: does IL-10 promotes exhaustion or prevents it? We hypothesize that PD1 blockade relieves CD8+ T cell exhaustion in an IL-10/IL-10R dependent manner. We will use the experimental paradigm of NME-exposure to test this hypothesis. Aim 1 is to establish the role for IL-10/IL-10R in supporting T cell function during aging. Aim2 is to determine the mechanism by which IL-10 supports T cell function in aged mice.

项目概要老年人是感染死亡的高危人群，其中流感和肺炎一直位列前茅是美国 65 岁以上老年人死亡的主要原因。入住 ICU 的老年人与医院死亡率相关。需要新的方法使老化的免疫系统恢复活力，促进感染的控制。我们利用实验将实验小鼠暴露于多种微生物的范例（称为正常微生物体验；NME）。 NME 激活幼鼠的免疫系统，增加功能性记忆 T 细胞。然而，在老年小鼠中， NME 暴露导致 100% 死亡率，随后出现细胞因子风暴和免疫浸润增加在多个组织中。现有证据表明，免疫衰老，包括炎症和免疫系统功能失调，在老年人感染的发病率中发挥着因果作用。疲惫是一个细胞老年人淋巴细胞增加，导致炎症、病毒持久性和组织病理学。它主要由慢性抗原暴露强制执行，但也受局部分泌因子，例如年轻人中的 IL-10。目前尚不清楚具体因素如何控制疲劳老年人感染之前和期间。我们推测IL-10，一种传统的抗炎药随着年龄的增长而积累的细胞因子，对 CD8 T 细胞也具有亲细胞毒性作用，是随着年龄的增长而疲惫不堪。该提案基于我们令人兴奋的初步数据，该数据描述了 PD1 的效果阻断，通过恢复 T 细胞活化来减少疲劳，并在该反应中涉及 IL-10。基于根据我们的数据，我们想知道：IL-10 是促进疲劳还是预防疲劳？我们假设 PD1 阻断以 IL-10/IL-10R 依赖性方式缓解 CD8+ T 细胞耗竭。我们将使用实验范式 NME 暴露来检验这一假设。目标 1 是确定 IL-10/IL-10R 在支持 T 细胞中的作用衰老过程中的功能。目的2是确定IL-10支持老年T细胞功能的机制老鼠。