Adaptive Liver Tolerance via LSECs
通过 LSEC 实现适应性肝脏耐受
基本信息
- 批准号:10221498
- 负责人:
- 金额:$ 38.88万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2018
- 资助国家:美国
- 起止时间:2018-09-19 至 2023-08-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAllogenicAnimal ModelAntigensAutoimmunityBasic ScienceBone MarrowCD4 Positive T LymphocytesCD8-Positive T-LymphocytesCell CommunicationCellsChronicChronic Hepatitis BClinicalComplexCross PresentationDataEmperipolesisEndothelial CellsFailureFunctional disorderGenesHepatitisHepatitis B VirusHepatitis C virusHepatocyteHomologous TransplantationImmuneImmune ToleranceImmunityImmunological ModelsImmunologicsIn VitroInterferon Type IIKupffer CellsLeadLiverMalignant NeoplasmsModelingMolecularMyeloid-derived suppressor cellsOutcomeParasitesPublishingRecoveryResearchResistanceSpleenSystemT-LymphocyteTestingTissuesTransgenesTranslational ResearchViral hepatitisVirusWorkadeno-associated viral vectoranergyantigen testbasechronic infectioncytokineexhaustionexperimental studyimmunopathologyin vivoliver transplantationlymph nodesmouse modelpathogenreceptorresponsesuicidal
项目摘要
Description
Antigens expressed in the liver frequently lead to T cell inactivation, resulting in failure to eliminate the
antigen. This is termed liver tolerance, was first described in the context of allogeneic liver transplants,
but also accounts for the failure to eliminate liver pathogens including viruses and parasites. Based on
published work and new Preliminary Data, we propose a unifying model which we term Adaptive Liver
Tolerance. Our central Premise is that Adaptive Liver Tolerance explains immune failure in the liver.
this model, hepatocellular antigens are presented directly to CD8+ T cells, but cross-presentation by
bone marrow-derived APCs does not occur. Thus, hepatocellular antigens can engage CD4+ T cells
only through cross-presentation by MHC-II+ tissue cells, for which the strongest candidates are liver
sinusoidal endothelial cells. However, our data show that liver sinusoidal endothelial cells strongly up-
regulate multiple immunosuppressive molecules. Therefore, the limited options for the cross-
presentation of hepatocellular antigens leads to CD4+ T cell tolerance, and thus to CD8+ T cell
exhaustion due to the lack of CD4+ T cell help. The immunosuppressive molecules that are expressed
on liver sinusoidal endothelial cells are IFN-gamma responsive. Therefore, in this project we will (1)
overcome the inactivation of CD4+ T cells, and test the prediction that this will reverse CD8+ T cell
dysfunction; (2) directly test the hypothesis that IFN-gamma acting on the liver sinusoidal endothelial
cells is the driver of the expression of immunosuppressive molecules, and of functional tolerance.
These experiments use an optimized model of immunity to an extrinsic hepatocellular antigen delivered
via an AAV vector, so we will also (3) test the applicability of the Adaptive Liver Tolerance model in a
mouse model of chronic HBV infection. If the hypothesis is supported, it will be rational to target liver
sinusoidal endothelial cells to promote tolerance in autoimmunity, and to break tolerance in chronic
infection. It will further suggest that, in some circumstances, inhibition of IFN-gamma will usefully
enhance immunity in the liver.
描述
在肝脏中表达的抗原经常导致T细胞失活,从而导致不能消除T细胞。
抗原的这被称为肝耐受,首先在同种异体肝移植的背景下描述,
而且也是未能消除包括病毒和寄生虫在内的肝脏病原体的原因。基于
发表的工作和新的初步数据,我们提出了一个统一的模型,我们称之为自适应肝脏
宽容我们的中心假设是适应性肝脏耐受解释了肝脏中的免疫失败。
在该模型中,肝细胞抗原直接呈递给CD 8 + T细胞,但通过CD 8 + T细胞交叉呈递,
骨髓来源的APC不发生。因此,肝细胞抗原可以接合CD 4 + T细胞
仅通过MHC-II+组织细胞的交叉呈递,其中最强的候选者是肝脏
窦状隙内皮细胞然而,我们的数据显示肝窦内皮细胞强烈上升-
调节多种免疫抑制分子。因此,交叉的选择有限-
肝细胞抗原的呈递导致CD 4 + T细胞耐受,并因此导致CD 8 + T细胞耐受。
由于缺乏CD 4 + T细胞的帮助而衰竭。表达的免疫抑制分子
对肝窦内皮细胞的作用是IFN-γ应答性的。因此,在本项目中,我们将(1)
克服了CD 4 + T细胞的失活,并测试了这将逆转CD 8 + T细胞的预测。
(2)直接验证IFN-γ作用于肝窦内皮细胞的假设,
细胞是免疫抑制分子表达和功能性耐受的驱动者。
这些实验使用了一个优化的模型,免疫外源性肝细胞抗原交付
因此,我们还将(3)在一个实验室中测试适应性肝耐受模型的适用性。
慢性HBV感染小鼠模型。如果该假设得到支持,则靶向肝脏将是合理的
窦内皮细胞,以促进自身免疫耐受,并打破慢性
感染这将进一步表明,在某些情况下,抑制IFN-γ将有益于
增强肝脏的免疫力。
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)
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Ian NICHOLAS Crispe其他文献
Ian NICHOLAS Crispe的其他文献
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{{ truncateString('Ian NICHOLAS Crispe', 18)}}的其他基金
NOVEL REVERSE ADJUVANT FOR VACCINE ENHANCEMENT
用于增强疫苗效果的新型反向佐剂
- 批准号:
7573075 - 财政年份:2009
- 资助金额:
$ 38.88万 - 项目类别:
NOVEL REVERSE ADJUVANT FOR VACCINE ENHANCEMENT
用于增强疫苗效果的新型反向佐剂
- 批准号:
7914396 - 财政年份:2009
- 资助金额:
$ 38.88万 - 项目类别:
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