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

• 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
• 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

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.

项目摘要 老年人感染死亡率的高风险，流感和肺炎始终排名 美国最高死亡原因是65岁以上的人。 与医院死亡率相关的ICU的老年人。需要新颖的方法 这使老化的免疫系统恢复活力，以促进感染的控制。我们利用实验 将实验小鼠暴露于多个微生物（称为正常微生物经验； NME）的范式。 NME激活了年轻小鼠的免疫系统，从而增加了功能性记忆T细胞。但是，在老鼠中， NME暴露导致100％死亡率，此前是细胞因子风暴和免疫浸润增加的死亡率 在多个组织中。现有证据表明，免疫衰老，包括炎症和 功能失调的免疫系统在对老年人感染的发病率中起因果作用。精疲力尽是一个细胞 来自老年人的淋巴细胞中增加的命运，这有助于炎症，病毒 持久性和组织病理学。它主要是由慢性抗原暴露执行的，但也受 当地分泌的因素，例如年轻人的IL-10。尚不清楚特定因素如何控制精疲力尽 老年人感染之前和期间。我们推测IL-10，一种传统的抗炎 随着年龄的增长而积累的细胞因子，并且对CD8 T细胞也具有促胞毒性作用，是调节剂 随着年龄的增长。该建议基于我们令人兴奋的初步数据，该数据描述了PD1的效果 封锁，通过恢复T细胞激活来减少疲惫，并在该响应中暗示IL-10。基于 在我们的数据上，我们想知道：IL-10是否会促进疲惫或阻止它？我们假设PD1封锁 以IL-10/IL-10R依赖性方式缓解CD8+ T细胞耗尽。我们将使用实验范式 NME暴露以检验该假设。 AIM 1是确定IL-10/IL-10R在支持T细胞中的作用 衰老期间的功能。 AIM2是确定IL-10支持T细胞功能的机制 老鼠。