Adaptive Liver Tolerance via LSECs

通过 LSEC 实现适应性肝耐受

基本信息

批准号：
10457946
负责人：
Ian NICHOLAS Crispe
金额：
$ 38.88万
依托单位：
UNIVERSITY OF WASHINGTON
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：
https://reporter.nih.gov/project-details/10457946
关键词：
Address Allogenic Animal Model Antigens Autoimmunity Basic Science Bone Marrow CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes Cell Communication Cells Chronic Chronic Hepatitis B Clinical Complex Cross Presentation Data Emperipolesis Endothelial Cells Failure Functional disorder Genes Hepatitis Hepatitis B Virus Hepatitis C virus Hepatocyte Homologous Transplantation Immune Immune Tolerance Immunity Immunological Models Immunologics In Vitro Interferon Type II Kupffer Cells Lead Liver Malignant Neoplasms Modeling Molecular Myeloid-derived suppressor cells Outcome Parasites Publishing Recovery Research Resistance Spleen System T-Lymphocyte Testing Tissues Transgenes Translational Research Viral hepatitis Virus Work adeno-associated viral vector anergy antigen test base chronic infection cytokine exhaustion experimental study immunopathology in vivo liver transplantation lymph nodes mouse model pathogen receptor response suicidal

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细胞灭活，导致未能消除抗原。这称为肝耐受性，首先是在同种异体肝移植的背景下描述的而且还解释了未能消除包括病毒和寄生虫在内的肝病病原体。基于已发表的工作和新的初步数据，我们提出了一个统一模型，我们称其为自适应肝宽容。我们的中心前提是自适应肝耐受解释了肝脏的免疫衰竭。该模型，肝细胞抗原直接呈现给CD8+ T细胞，但通过没有发生骨髓来源的APC。因此，肝细胞抗原可以参与CD4+ T细胞仅通过MHC-II+组织细胞的交叉表达，最强的候选者是肝脏正弦内皮细胞。但是，我们的数据表明，肝脏正弦内皮细胞强烈上升 - 调节多种免疫抑制分子。因此，交叉的有限选择肝细胞抗原的表现会导致CD4+ T细胞的耐受性，从而导致CD8+ T细胞由于缺乏CD4+ T细胞的帮助而疲惫。表达的免疫抑制分子在肝脏正弦的内皮细胞上具有IFN-GAMMA的反应。因此，在这个项目中，我们将（1）克服CD4+ T细胞的灭活，并测试这将逆转CD8+ T细胞的预测功能障碍；（2）直接检验以下假设：IFN-gamma作用于肝脏正弦内皮细胞是免疫抑制分子表达和功能耐受性的驱动力。这些实验使用对递送外部肝细胞抗原的优化免疫模型通过AAV矢量，我们还将（3）测试自适应肝公差模型的适用性慢性HBV感染的小鼠模型。如果支持假设，则靶向肝脏是合理的正弦内皮细胞以促进自身免疫性的耐受性，并破坏慢性的耐受性感染。这将进一步表明，在某些情况下，抑制IFN-Gamma会有用增强肝脏的免疫力。