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:
- 金额:$ 22.61万
- 依托单位:
- 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:
- 关键词:2019-nCoVAddressAdoptive TransferAffectAgeAgingAnti-Inflammatory AgentsAntigensCD8-Positive T-LymphocytesCOVID-19 pandemicCause of DeathCell modelCell physiologyCellsCellular Indexing of Transcriptomes and Epitopes by SequencingChronicChronic DiseaseCombined Modality TherapyComplementDataElderlyExposure toFoundationsFutureGene Expression ProfileGenesGoalsHospital MortalityHospitalizationHumanImmuneImmune systemImmunotherapyIn VitroIndividualInfectionInfection ControlInflammagingInfluenzaInterleukin-10Knock-outLymphocyteLymphocyte SubsetMeasuresMicrobeMorbidity - disease rateMusPD-1 blockadePI3 genePathologyPathway interactionsPatientsPlayPneumoniaProto-Oncogene Proteins c-aktReceptor ActivationReceptor SignalingRecombinantsRiskRoleSTAT3 geneSepsisSignal PathwaySignal TransductionSourceStainsT memory cellT-Cell ActivationT-Cell ReceptorT-LymphocyteTestingTherapeutic UsesTissuesTranscriptional ActivationTranslationsTumor-infiltrating immune cellsVirusWorkagedbasecancer immunotherapycell typechronic infectionco-infectioncytokinecytokine release syndromecytotoxicdifferential expressioneffector T cellexhaustexhaustionexperiencehigh riskimmunosenescenceimprovedimproved outcomeinfectious disease treatmentinfluenza pneumoniamicrobialmortalitymortality riskmouse modelnovel strategiesnovel therapeuticspreventprogrammed cell death protein 1protective effectresponseseasonal influenzasecondary infectionsevere COVID-19young 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
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Christina Camell其他文献
Christina Camell的其他文献
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{{ truncateString('Christina Camell', 18)}}的其他基金
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:
10704181 - 财政年份:2022
- 资助金额:
$ 22.61万 - 项目类别:
Role of adipose tissue inflammaging and metabolic dysfunction during sepsis
脓毒症期间脂肪组织炎症和代谢功能障碍的作用
- 批准号:
10563704 - 财政年份:2022
- 资助金额:
$ 22.61万 - 项目类别:
Macrophage inflammasome activation and the mechanism of lipolysis resistance in aged adipose
老年脂肪巨噬细胞炎症小体激活及抗脂解机制
- 批准号:
10121181 - 财政年份:2019
- 资助金额:
$ 22.61万 - 项目类别:
Macrophage inflammasome activation and the mechanism of lipolysis resistance in aged adipose
老年脂肪巨噬细胞炎症小体激活及抗脂解机制
- 批准号:
10190757 - 财政年份:2019
- 资助金额:
$ 22.61万 - 项目类别:
Macrophage inflammasome activation and the mechanism of lipolysis resistance in aged adipose
老年脂肪巨噬细胞炎症小体激活及抗脂解机制
- 批准号:
10012936 - 财政年份:2019
- 资助金额:
$ 22.61万 - 项目类别:
Early inflammatory responses to high saturated fat diet
高饱和脂肪饮食的早期炎症反应
- 批准号:
8137833 - 财政年份:2009
- 资助金额:
$ 22.61万 - 项目类别:
Early inflammatory responses to high saturated fat diet
高饱和脂肪饮食的早期炎症反应
- 批准号:
8329014 - 财政年份:2009
- 资助金额:
$ 22.61万 - 项目类别:
Early inflammatory responses to high saturated fat diet
高饱和脂肪饮食的早期炎症反应
- 批准号:
8025921 - 财政年份:2009
- 资助金额:
$ 22.61万 - 项目类别:
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