B-Cell Dysregulation in Cirrhosis due to Chronic Hepatitis C Infection
慢性丙型肝炎感染引起的肝硬化中的 B 细胞失调
基本信息
- 批准号:8633581
- 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:2014
- 资助国家:美国
- 起止时间:2014-01-01 至 2017-09-30
- 项目状态:已结题
- 来源:
- 关键词:AffectAlcohol consumptionAmericanAntibodiesAntibody FormationAntiviral TherapyApoptosisApoptoticAutomobile DrivingB Cell ProliferationB-Cell ActivationB-Lymphocyte SubsetsB-LymphocytesBacterial InfectionsBacterial TranslocationBlood specimenCD95 AntigensCell SurvivalCell physiologyCellsCessation of lifeCharacteristicsChronicChronic Hepatitis CCirrhosisClinicalClinical ManagementComplement 3d ReceptorsCross-Sectional StudiesDataDefectDevelopmentDiabetes MellitusDiseaseDisease ProgressionEtiologyFailureFrequenciesFunctional disorderGoalsHIVHealthHealth Care CostsHepatitis B VirusHepatitis CHepatitis C virusHomeostasisHumanHuman IdentificationsHumoral ImmunitiesImmuneImmunityImmunocompromised HostImmunoglobulin MImmunoglobulinsIn VitroIndividualInfectionInterventionInvestigationLeadLiverLiver CirrhosisLiver FibrosisLymphocyte FunctionMaintenanceMediatingMemoryMemory B-LymphocyteMorbidity - disease rateMusObesityPathogenesisPatientsPeritonitisPhenotypePhysiologyPlasmaPlayPopulationPortal HypertensionPredispositionPrevention strategyPrimary carcinoma of the liver cellsProspective StudiesReceptors, Antigen, B-CellRelative (related person)ResearchResolutionRestRiskRoleSepsisSignal PathwayStagingSyndromeT-LymphocyteTNFRSF5 geneTNFRSF6 geneTherapeuticTimeTissue SampleTumor AntigensVaccinesVeteransViralViremiaVirusVirus DiseasesWorkantimicrobialbasecancer preventioncohortcytokineexhaustexhaustionhuman subjectimprovedin vivoinsightliver transplantationmicrobialmortalitynovelpathogenpublic health relevancereceptorreceptor expressiontranslational study
项目摘要
DESCRIPTION (provided by applicant):
Hepatitis C infection affects approximately 3.9 million Americans and disproportionately impacts the health of veterans. Approximately one-third of infected individuals will develop progressive liver fibrosis culminating in cirrhosis. Bacterial infections and sepsis are prominent causes of morbidity and mortality in patients with cirrhosis. Susceptibility to infections in cirrhosis has largely been attributed to increased bacterial translocation across the gut in the setting of reduced innate immune protective mechanisms. Additionally, antibody responses to vaccines have been long established to be inefficient in cirrhotic patients, suggesting a defect in B-cell activation. However, the contribution of B-cell dysfunction to the cirrhotic immunocompromised state has largely remained unexplored. Our novel preliminary data demonstrate that cirrhosis is associated with the disappearance of CD27+ memory B-cells, leading to impaired B-cell activation and reduced capacity of B-cells to stimulate T-cells. Preliminary investigation suggests that soluble factors elevated in cirrhotic plasma may lead to B-cell hyperactivation, that
Fas expression is markedly increased on CD27+ B-cells and expression of pro-survival receptors such as CD268/BAFF-R are reduced. We hypothesize that chronic hyperactivation due to gut translocation leads to either activation-induced apoptosis of memory B-cells or conversion to an "exhausted" CD27-CD21- memory B-cells population with weak effector capacity. The objectives of this proposal are to longitudinally confirm the association of B-cell dysfunction and cirrhosis identified in cross-sectional studies, to study the impact of cirrhosis o B-cell proliferation and apoptosis, and to explore approaches to reverse this dysfunction in vivo in translational studies. The research encompasses in vitro studies on B-lymphocyte function using blood and tissue samples donated by human subjects in addition to prospective studies of B-cell memory frequency with and without clinical interventions. First, we will examine if the loss
of CD27+ B-cells in cirrhosis reflects specific deletion of innate B1-type B-cells critical for protection against bacterial sepsis. Second, we will examine activation of signal pathways such as NF B downstream of CD40, BAFF-R and TLR9 on the activation of CD27+ B-cells in cirrhosis relative to healthy donors. Lastly, we will longitudinally follow the phenotype and function of B-cells in after pharmacological reduction of bacterial translocation, cure of HCV viremia, and in the peritransplant setting to assess the impact of gut translocation, portal hypertension and viremia on maintenance of B-cell dysfunction in cirrhotic patients. The ultimate goal of these studies is to identify conditions under which cirrhotic patient B-cells function can be improved in
vivo to reduce the morbidity and mortality of infectious complications of cirrhosis.
描述(由申请人提供):
项目成果
期刊论文数量(0)
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David E Kaplan其他文献
Top tagging: a method for identifying boosted hadronically decaying top quarks.
顶标记:一种识别增强强子衰变顶夸克的方法。
- DOI:
- 发表时间:
2008 - 期刊:
- 影响因子:8.6
- 作者:
David E Kaplan;Keith R. Rehermann;Matthew D Schwartz;B. Tweedie - 通讯作者:
B. Tweedie
David E Kaplan的其他文献
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{{ truncateString('David E Kaplan', 18)}}的其他基金
Cross-comparison of patient-derived xenografts and derivative organoids and cell lines for translational research in hepatocellular carcinoma
患者来源的异种移植物和衍生类器官和细胞系的交叉比较,用于肝细胞癌的转化研究
- 批准号:
10041707 - 财政年份:2020
- 资助金额:
-- - 项目类别:
Effect of simvastatin on hepatic decompensation and death in subjects with high-risk compensated cirrhosis
辛伐他汀对高危代偿性肝硬化受试者肝代偿失调和死亡的影响
- 批准号:
10578754 - 财政年份:2020
- 资助金额:
-- - 项目类别:
Effect of simvastatin on hepatic decompensation and death in subjects with high-risk compensated cirrhosis
辛伐他汀对高危代偿性肝硬化受试者肝代偿失调和死亡的影响
- 批准号:
10464880 - 财政年份:2020
- 资助金额:
-- - 项目类别:
Cross-comparison of patient-derived xenografts and derivative organoids and cell lines for translational research in hepatocellular carcinoma
患者来源的异种移植物和衍生类器官和细胞系的交叉比较,用于肝细胞癌的转化研究
- 批准号:
9776808 - 财政年份:2020
- 资助金额:
-- - 项目类别:
Tumor antigen-specific T-cells and hepatocellular carcinoma
肿瘤抗原特异性 T 细胞和肝细胞癌
- 批准号:
8438826 - 财政年份:2013
- 资助金额:
-- - 项目类别:
Tumor antigen-specific T-cells and hepatocellular carcinoma
肿瘤抗原特异性 T 细胞和肝细胞癌
- 批准号:
8821484 - 财政年份:2013
- 资助金额:
-- - 项目类别:
Engineered lymphocytes for the treatment of hepatocellular carcinoma
用于治疗肝细胞癌的工程化淋巴细胞
- 批准号:
8046329 - 财政年份:2010
- 资助金额:
-- - 项目类别:
Engineered lymphocytes for the treatment of hepatocellular carcinoma
用于治疗肝细胞癌的工程化淋巴细胞
- 批准号:
7874043 - 财政年份:2010
- 资助金额:
-- - 项目类别:
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