Defining the intrahepatic immune response to hepatitis C virus
定义对丙型肝炎病毒的肝内免疫反应
基本信息
- 批准号:7781668
- 负责人:
- 金额:$ 43.72万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2010
- 资助国家:美国
- 起止时间:2010-04-01 至 2014-03-31
- 项目状态:已结题
- 来源:
- 关键词:Animal ModelAntigen PresentationAntigen-Presenting CellsAntiviral AgentsApoptosisAreaBiological AssayBiological ModelsCD4 Positive T LymphocytesCD8B1 geneCell CommunicationCell physiologyCellsCessation of lifeChronicCirrhosisDataDependenceDevelopmentDisease ProgressionEragrostisEventExperimental ModelsFailureFamilyFigs - dietaryFlow CytometryFunctional disorderFutureHepatic FibrogenesisHepatic Stellate CellHepatitis CHepatitis C virusHepatocyteHumanImmuneImmune responseImmunityIndividualInfectionInjury to LiverInvestigationKineticsKnockout MiceLiverLiver FibrosisLiver diseasesMediatingModelingMolecularMusOutcomePatientsPerisinusoidal SpacePhenotypePlayPopulationPositioning AttributePrimary carcinoma of the liver cellsProcessProductionProteinsPublishingRefractoryRegulatory T-LymphocyteRoleSamplingSignal TransductionSpecimenStagingStimulusT cell differentiationT cell responseT-LymphocyteTherapeuticTretinoinUnited StatesViralViral AntigensViral ProteinsVirusVirus DiseasesWorkcytokineexhaustin vitro Modelin vivoinhibitor/antagonistinterestintrahepaticliver transplantationnovelperipheral bloodprogramsprophylacticpublic health relevanceresponsesmall molecule
项目摘要
DESCRIPTION (provided by applicant): Infection with hepatitis C virus (HCV) results in persistent liver disease in the majority of infected individuals and HCV-associated end-stage liver disease is now the leading indication for liver transplantation in the United States. Many studies have highlighted the importance of the T cell response for viral clearance and attributed persistent infection to an insufficient T cell response. However, in persistent HCV infection the factors leading to immune failure are not clear. We recently published work showing that the intrahepatic HCV-specific T cell response in chronically infected human patients does not mirror the response in the peripheral blood and that, in fact, phenotypically exhausted T cells characterize the liver infiltrating population. Accordingly, we postulate that in the natural course of HCV infection, viral persistence is a direct result of the inadequacy of the intrahepatic immune response and more specifically, that intrahepatic antigen presenting cells (APCs) modulate and impair the antiviral T cell response thereby contributing to viral persistence. Hepatic stellate cells (HSC) are a novel population of intrahepatic APC that undergo dramatic phenotypic and functional changes in response to liver injury or infection. This process is known to be important for liver fibrogenesis, but little is known of the importance of HSC as APCs and how APC function is changed during HCV infection. Our preliminary work indicates a transition from immunostimulatory to immunoinhibitory function upon activation of HSC. Thus, the work proposed here will focus on HSC and their ability to modulate T cell immunity through viral antigen presentation in the context of costimulatory or coinhibitory molecules and the influence that HCV has on this process. We will dissect the pair-wise relationships between HSC and T cells, HSC and HCV, while bringing together all three factors to determine the impact of this tripartite interaction on the outcome of HCV infection. We expect to find that HSC play a role in the intrahepatic T cell dysfunction during HCV infection and therefore promote persistent infection.
PUBLIC HEALTH RELEVANCE: Hepatitis C virus (HCV)-induced chronic liver disease with associated cirrhosis and hepatocellular carcinoma is now the leading indication for liver transplantation in the United States. There are currently an estimated 170 million HCV carriers worldwide and nearly 3 million in the U.S. (~2% of the population). We are seeking to elucidate and understand the mechanisms by which the host immune response fails in the majority of those infected and to future efforts to develop prophylactic and/or therapeutic HCV eradication strategies.
描述(申请人提供):感染丙型肝炎病毒(丙型肝炎病毒)会导致大多数感染者的持续性肝病,丙型肝炎病毒相关的终末期肝病现在是美国肝脏移植的主要适应症。许多研究强调了T细胞反应对病毒清除的重要性,并将持续感染归因于T细胞反应不足。然而,在持续性的丙型肝炎病毒感染中,导致免疫失败的因素尚不清楚。我们最近发表的工作表明,在慢性感染的人类患者中,肝内丙型肝炎病毒特异性T细胞反应并不反映外周血中的反应,事实上,表型耗尽的T细胞是肝脏浸润性人群的特征。因此,我们推测,在丙型肝炎病毒感染的自然过程中,病毒持续存在是肝内免疫反应不足的直接结果,更具体地说,是肝内抗原提呈细胞(APC)调节和损害抗病毒T细胞反应,从而促进病毒持续存在。肝星状细胞(HSC)是一种新型的肝内APC,在肝脏损伤或感染时会发生显著的表型和功能变化。已知这一过程对肝纤维化的形成很重要,但对HSC作为APC的重要性以及APC功能在丙型肝炎病毒感染过程中如何改变知之甚少。我们的初步工作表明,当HSC被激活时,免疫刺激功能向免疫抑制功能转变。因此,本文建议的工作将集中在HSC及其在共刺激或共抑制分子背景下通过病毒抗原提呈来调节T细胞免疫的能力,以及丙型肝炎病毒对这一过程的影响。我们将剖析HSC和T细胞、HSC和丙型肝炎病毒之间的配对关系,同时结合所有这三个因素来确定这种三方交互作用对丙型肝炎病毒感染结局的影响。我们期望发现HSC在丙型肝炎病毒感染时肝内T细胞功能障碍中发挥作用,从而促进持续感染。
公共卫生相关性:丙型肝炎病毒(丙型肝炎病毒)引起的慢性肝病伴发肝硬变和肝细胞癌目前是美国肝移植的主要适应症。目前,全球估计有1.7亿丙型肝炎病毒携带者,美国有近300万人(约占总人口的2%)。我们正在寻求阐明和了解大多数感染者宿主免疫反应失败的机制,以及未来制定预防和/或治疗性根除丙型肝炎策略的努力。
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)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Arash Grakoui其他文献
Arash Grakoui的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('Arash Grakoui', 18)}}的其他基金
Correlates of protective immunity to HCV and rational vaccine design
HCV 保护性免疫与合理疫苗设计的相关性
- 批准号:
10393614 - 财政年份:2021
- 资助金额:
$ 43.72万 - 项目类别:
Correlates of protective immunity to HCV and rational vaccine design: Admin Core
HCV 保护性免疫与合理疫苗设计的相关性:Admin Core
- 批准号:
10393615 - 财政年份:2021
- 资助金额:
$ 43.72万 - 项目类别:
Correlates of protective immunity to HCV and rational vaccine design
HCV 保护性免疫与合理疫苗设计的相关性
- 批准号:
10205764 - 财政年份:2021
- 资助金额:
$ 43.72万 - 项目类别:
Correlates of protective immunity to HCV and rational vaccine design: Project 2
HCV 保护性免疫与合理疫苗设计的相关性:项目 2
- 批准号:
10205768 - 财政年份:2021
- 资助金额:
$ 43.72万 - 项目类别:
Correlates of protective immunity to HCV and rational vaccine design: Project 2
HCV 保护性免疫与合理疫苗设计的相关性:项目 2
- 批准号:
10393618 - 财政年份:2021
- 资助金额:
$ 43.72万 - 项目类别:
Correlates of protective immunity to HCV and rational vaccine design: Project 2
HCV 保护性免疫与合理疫苗设计的相关性:项目 2
- 批准号:
10608110 - 财政年份:2021
- 资助金额:
$ 43.72万 - 项目类别:
Correlates of protective immunity to HCV and rational vaccine design
HCV 保护性免疫与合理疫苗设计的相关性
- 批准号:
10608105 - 财政年份:2021
- 资助金额:
$ 43.72万 - 项目类别:
Correlates of protective immunity to HCV and rational vaccine design: Admin Core
HCV 保护性免疫与合理疫苗设计的相关性:Admin Core
- 批准号:
10205765 - 财政年份:2021
- 资助金额:
$ 43.72万 - 项目类别:
Correlates of protective immunity to HCV and rational vaccine design: Admin Core
HCV 保护性免疫与合理疫苗设计的相关性:Admin Core
- 批准号:
10608106 - 财政年份:2021
- 资助金额:
$ 43.72万 - 项目类别:
Dynamics of antigen specific B and Tfh responses during acute and chronic HCV
急性和慢性 HCV 期间抗原特异性 B 和 Tfh 反应的动态
- 批准号:
10063938 - 财政年份:2017
- 资助金额:
$ 43.72万 - 项目类别:
相似海外基金
Defining MHC class I restricted antigen presentation to CD8 T cells in experimental AD and Tauopathy - Supplement
定义实验性 AD 和 Tau 病中 MHC I 类限制性抗原呈递至 CD8 T 细胞 - 补充
- 批准号:
10836880 - 财政年份:2023
- 资助金额:
$ 43.72万 - 项目类别:
Targeting MAL2-mediated endocytosis to enhance tumor cell antigen presentation
靶向 MAL2 介导的内吞作用以增强肿瘤细胞抗原呈递
- 批准号:
10734324 - 财政年份:2023
- 资助金额:
$ 43.72万 - 项目类别:
Antigen presentation to the adaptive immune system in the choroid contributes to ocular autoimmune disease
脉络膜中的适应性免疫系统的抗原呈递导致眼部自身免疫性疾病
- 批准号:
10740465 - 财政年份:2023
- 资助金额:
$ 43.72万 - 项目类别:
Investigation of Target Protein Degradation and Its Effect on Enhancing Cancer-Specific Antigen Presentation by Quantitative Mass Spectrometry
通过定量质谱研究靶蛋白降解及其对增强癌症特异性抗原呈递的影响
- 批准号:
23K04971 - 财政年份:2023
- 资助金额:
$ 43.72万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Promoting cancer cells' antigen presentation for serving as better targets for T cell immunotherapy
促进癌细胞的抗原呈递,作为 T 细胞免疫治疗的更好靶点
- 批准号:
2885451 - 财政年份:2023
- 资助金额:
$ 43.72万 - 项目类别:
Studentship
Targeting immunoproteasome-mediated antigen presentation in colorectal cancer immunotherapy
结直肠癌免疫治疗中靶向免疫蛋白酶体介导的抗原呈递
- 批准号:
10385926 - 财政年份:2022
- 资助金额:
$ 43.72万 - 项目类别:
Lipid Antigen Presentation as a Driver of T2D Inflammation
脂质抗原呈递作为 T2D 炎症的驱动因素
- 批准号:
10509043 - 财政年份:2022
- 资助金额:
$ 43.72万 - 项目类别:
Enhancing antigen presentation in triple negative breast cancers through CD40 agonist, Flt3 ligand, and anthracycline chemotherapy
通过 CD40 激动剂、Flt3 配体和蒽环类化疗增强三阴性乳腺癌的抗原呈递
- 批准号:
10704008 - 财政年份:2022
- 资助金额:
$ 43.72万 - 项目类别:
Sex Differences in lipid antigen presentation, impact of lipid antigen presentation on peripheral lipid metabolism
脂质抗原呈递的性别差异,脂质抗原呈递对外周脂质代谢的影响
- 批准号:
10818273 - 财政年份:2022
- 资助金额:
$ 43.72万 - 项目类别:
Enhancing antigen presentation in triple negative breast cancers through CD40 agonist, Flt3 ligand, and anthracycline chemotherapy
通过 CD40 激动剂、Flt3 配体和蒽环类化疗增强三阴性乳腺癌的抗原呈递
- 批准号:
10349397 - 财政年份:2022
- 资助金额:
$ 43.72万 - 项目类别: