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 老年人因感染而死亡的风险很高，流感和肺炎一直排在 是美国65岁以上人群的主要死因同时感染的比率也有所增加， 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，以促进对感染的控制。我们利用一个实验性的 将实验小鼠暴露于多种微生物的范式（称为正常微生物体验; NME）。 NME激活年轻小鼠的免疫系统，增加功能性记忆T细胞。然而，在老年小鼠中， NME暴露导致100%的死亡率，之前是细胞因子风暴和免疫浸润增加 在多个组织中。现有的证据表明，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因果作用。疲惫是一个细胞 在老年人淋巴细胞中增加的命运，并有助于炎症，病毒 持久性和组织病理学。它主要通过慢性抗原暴露来实施，但也受到以下因素的调节： 局部分泌因子，如年轻个体中的IL-10。具体因素如何控制衰竭尚不清楚 在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，也对CD 8 T细胞具有促细胞毒性作用，是CD 8 T细胞的调节因子。 随着年龄的增长而疲惫。该建议基于我们令人兴奋的初步数据，该数据描述了PD 1的影响， 阻断，其通过恢复T细胞活化来减少衰竭，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PD 1阻断 以IL-10/IL-10 R依赖性方式缓解CD 8 + T细胞耗竭。我们将使用实验范例 来检验这一假设。目的1：探讨IL-10/IL-10 R在T细胞免疫中的作用 在老化过程中发挥作用。目的2是确定IL-10在老年人中支持T细胞功能的机制。 小鼠