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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.

项目总结