Role of IL-6 and IL-1b in immune dysfunction during aging, HIV, and HCV infection
IL-6 和 IL-1b 在衰老、HIV 和 HCV 感染期间免疫功能障碍中的作用
基本信息
- 批准号:9858239
- 负责人:
- 金额:--
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2017
- 资助国家:美国
- 起止时间:2017-01-01 至 2021-12-31
- 项目状态:已结题
- 来源:
- 关键词:Activities of Daily LivingAgeAgingAmericanAntigensAntiviral TherapyCardiovascular DiseasesCaringCell AgingCell Culture TechniquesCell ProliferationCell SeparationCell physiologyCellsChronicChronic Hepatitis CCultured CellsDataDevelopmentElderlyExcisionExposure toFlow CytometryFunctional disorderGoalsHIVHIV InfectionsHIV/HCVHealthHepatitis CHepatitis C virusHomeostasisHumanIL6 geneIL7 geneImmuneImmune System DiseasesImmune systemImmunologic MarkersIn VitroIndividualInfectionInflammationInflammation MediatorsInflammatoryInterferonsInterleukin-1 betaInterleukin-6K-Series Research Career ProgramsLate EffectsLeftLiver diseasesLymphocytic choriomeningitis virusMalignant NeoplasmsMeasuresMorbidity - disease ratePatientsPeripheral Blood Mononuclear CellPhenotypePlasmaPopulationProductionProliferatingProteinsProviderRecoveryResearchResearch PersonnelRheumatoid ArthritisRoleSystemT-LymphocyteTestingTherapeuticTherapeutic InterventionUp-RegulationVeteransViralVirusVirus DiseasesVirus Replicationagedantiretroviral therapybasecareerchronic infectioncomorbiditycytokinedesignexhaustexhaustionhuman old age (65+)immune functionimmune healthimprovedinsightliver injurylymph nodesmilitary veteranmortalitymouse modelnovel strategiesolder patientpatient populationprogrammed cell death protein 1programsresponsesenescencesystemic inflammatory responsetargeted treatmenttherapeutic target
项目摘要
Chronic systemic inflammation is associated with immune dysfunction and morbidities in the elderly, treated
HIV infection, and HCV infection. We propose that circulating inflammatory proteins drive immune exhaustion
and senescence and contribute to the immune dysfunction seen in these patient groups. Nearly 4 million
Americans are infected with Hepatitis C Virus (HCV) and the mean age of US veterans infected with HCV is
nearing 65 years. Although the new IFN-free direct-acting antiviral therapy is highly effective at clearing virus
from patients, the patients are left with the consequences of decades of infection and liver damage, and it is
still unclear how long soluble mediators of inflammation persist, and how long immune dysfunction and
associated morbidity lasts. Similarly, even HIV-infected patients that have successfully controlled viral
replication with ART for decades have increased mortality and morbidity and persistent inflammation. The VA
is the largest single provider of HIV care in the US. Understanding what causes the continued morbidity in
these veteran patient populations is critical. The elderly, HCV and HIV-infected patients all have chronic
immune inflammation and these three patient groups share many of the same comorbidities including
cardiovascular disease, cancer, and liver disease. The project design of this CDA-2 application is based on the
understanding that patients with chronic viral infections and elderly patients show chronic elevated plasma
levels of IL-6, and our more recent data demonstrating elevated levels of IL-1β in lymph nodes of HIV-infected
patients. The central goals of this study are to determine the underlying mechanisms of IL-6 and IL-1β that
contribute to the development of immune exhaustion and senescence and to examine the potential therapeutic
role of temporarily blocking IL-6 and IL-1β during chronic infection to improve immune function and recovery of
exhausted or senescent T cells. The hypothesis that chronic elevated levels of IL-6 and IL-1β during aging,
HCV infection and HIV infection contribute to immune senescence and exhaustion and resulting immune
dysfunction will be tested in 3 specific Aims. Aim 1 will determine the phenotype and function of T cells that
have been exposed to IL-1β or IL-6 in vitro by sorting the cells positive for exhaustion or senescent markers
(PD-1, CD57, Tim-3, KLRG1, Lag3) and examining their functional abilities to determine if inflammatory
cytokines alone can drive senescence, independent of antigen exposure. Aim 2A will examine the expression
levels of exhaustion and senescent markers and the intracellular production of cytokines associated with the
senescence-associated secretory phenotype (SASP) in lymphocytess from HCV-infected, treated HIV-infected,
and elderly patients by flow cytometry. Aim 2B will examine the recovery and normalization of immune
function, longitudinally, in HIV-infected patients after initiation of ART and in HCV-infected patients after
initiation of IFN-free direct-acting antiviral therapy. In Aim 3 we will use a mouse model of chronic viral
infection (LCMV) to determine the effect of late blockade of IL-6 and IL-1β on the development of exhausted
and senescent T cells, and the recovery of T cell function and proliferative ability. The candidate's long term
goals are to understand the effects of chronic inflammation on health, the mechanisms by which the immune
system maintains homeostasis, and how inflammation disrupts the ability of the immune system to reestablish
homeostasis after infection and during aging. This focus supports a growing need nationwide to advance our
understanding and develop therapeutic strategies in the aging veteran population with and without chronic viral
infection. The candidate's career goals are to use this Career Development Award to successfully transition to
an independent investigator at the Louis Stokes Cleveland VAMC, and to establish a productive, thriving,
national leading research program in the VA system.
慢性全身性炎症与老年人的免疫功能障碍和发病率有关,治疗
项目成果
期刊论文数量(0)
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会议论文数量(0)
专利数量(0)
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Carey Lynn Shive其他文献
Carey Lynn Shive的其他文献
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{{ truncateString('Carey Lynn Shive', 18)}}的其他基金
Impact of preexisting immune profile in elderly on influenza vaccine response
老年人原有免疫特征对流感疫苗反应的影响
- 批准号:
10485431 - 财政年份:2022
- 资助金额:
-- - 项目类别:
COVID19: Respiratory SARS-CoV-2 seroprevalence and the association of humoral immune responses with clinical outcomes in veterans and employees in the Cleveland VA Medical Center
COVID19:克利夫兰退伍军人医疗中心退伍军人和员工的呼吸道 SARS-CoV-2 血清流行率以及体液免疫反应与临床结果的关联
- 批准号:
10160554 - 财政年份:2021
- 资助金额:
-- - 项目类别:
COVID19: Respiratory SARS-CoV-2 seroprevalence and the association of humoral immune responses with clinical outcomes in veterans and employees in the Cleveland VA Medical Center
COVID19:克利夫兰退伍军人医疗中心退伍军人和员工的呼吸道 SARS-CoV-2 血清流行率以及体液免疫反应与临床结果的关联
- 批准号:
10359116 - 财政年份:2021
- 资助金额:
-- - 项目类别:
Role of IL-6 and IL-1b in immune dysfunction during aging, HIV, and HCV infection
IL-6 和 IL-1b 在衰老、HIV 和 HCV 感染期间免疫功能障碍中的作用
- 批准号:
10291768 - 财政年份:2017
- 资助金额:
-- - 项目类别:
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