Liver Dendritic Cells in Tolerance and Immunity

肝树突状细胞的耐受性和免疫

• 批准号: 6815631
• 负责人: Ronald P Dematteo
• 金额: $ 33.4万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-09-01 至 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6815631
• 关键词: CpG islands; T lymphocyte; anergy; biological models; cell cell interaction; cell mediated lymphocytolysis test; delayed hypersensitivity; dendritic cells; flow cytometry; gene targeting; genetically modified animals; immune tolerance /unresponsiveness; immunity; immunocytochemistry; laboratory mouse; liver; model design /development; spleen

DESCRIPTION (provided by applicant): The liver is unique in its immunologic properties. Although dendritic cells (DC) are known to be critical regulators of the immune system, little is known about normal liver DC. We have determined that bulk murine liver DC are functionally distinct from bulk spleen DC. We have also identified 5 subtypes of freshly isolated liver DC. One subtype is plasmacytoid DC, which we found to be relatively abundant in the liver as compared to the spleen. We have discovered that liver and spleen plasmacytoid DC have disparate function. Steady state liver plasmacytoid DC are less mature and induce less allogeneic and antigen specific T cell activation. Upon stimulation, liver plasmacytoid DC secrete large amounts of TNF-alpha and IFN-alpha unlike spleen plasmacytoid DC, which make large quantities of IL-10. We hypothesize that liver plasmacytoid DC normally contribute to tolerance in the liver. However, because liver plasmacytoid DC can be stimulated to secrete pro-inflammatory cytokines, we postulate that they are also capable of inducing immunity. In Aim 1, we will determine the mechanism of interaction between liver plasmacytoid DC and T cells. We will employ an established murine model of intravenous adoptive transfer of TCR transgenic T cells and footpad injection of dendritic cells. We will determine if liver plasmacytoid DC induce T cell anergy, deletion, or suppression by studying the T helper response and delayed type hypersensitivity reaction. In Aim 2, we will ascertain whether liver plasmacytoid DC are necessary for liver tolerance by developing a model of injecting antigen loaded liver plasmacytoid DC into the portal vein of mice. We will also directly test the importance of liver plasmacytoid DC in portal vein tolerance in vivo by using a depleting antibody. In Aim 3, we will study the mechanism of interaction between stimulated liver plasmacytoid DC and T cells and how it is affected by DC cytokine secretion. We will determine whether stimulation of liver plasmacytoid DC prevents their induction of tolerance. The proposed experiments will define further the biology of liver dendritic cells and their interaction with T cells, as well as advance our understanding of tolerance and immunity. We expect the findings to be important for immunologic conditions of the liver that include autoimmunity, infection, transplantation, and cancer.

描述（由申请人提供）：肝脏在其免疫学特性中是独一无二的。尽管已知树突状细胞（DC）是免疫系统的关键调节剂，但对正常肝脏DC知之甚少。我们已经确定大量鼠肝脏DC在功能上与散装脾脏DC不同。我们还确定了5个新鲜分离的肝直流的亚型。一种亚型是浆细胞类动物DC，与脾脏相比，我们发现肝脏相对丰富。我们发现肝脏和脾纤溶酶DC具有不同的功能。稳态肝浆细胞类动物DC不太成熟，诱导同种异体和抗原特异性T细胞活化。刺激后，与脾浆细胞乳突DC不同，肝脏纤维细胞类动物DC分泌了大量的TNF-α和IFN-α，它们会产生大量的IL-10。我们假设肝浆纤维细胞类动物DC通常有助于肝脏的耐受性。但是，由于可以刺激肝浆细胞类动物DC来分泌促炎性细胞因子，因此我们假设它们也能够诱导免疫力。在AIM 1中，我们将确定肝浆细胞类动物DC和T细胞之间相互作用的机理。我们将采用既定的TCR转基因T细胞静脉内产物转移和树突状细胞注射脚踏板的植物模型。我们将通过研究T辅助反应和延迟类型的超敏反应来确定肝浆细胞类动物DC是否会诱导T细胞的消除，缺失或抑制。在AIM 2中，我们将通过开发一种将抗原负载的肝纤溶酶DC开发到小鼠门静脉的模型来确定肝纤溶酶DC是否对于肝耐受是必需的。我们还将通过使用耗尽的抗体直接测试肝浆细胞类动物DC在体内耐受性中的重要性。在AIM 3中，我们将研究刺激的肝纤溶酶DC和T细胞之间相互作用的机制，以及它如何受到DC细胞因子分泌的影响。我们将确定刺激肝细胞肽直流是否可以防止其耐受性诱导。提出的实验将进一步定义肝树突状细胞的生物学及其与T细胞的相互作用，并提高我们对耐受性和免疫力的理解。我们希望发现对于包括自身免疫，感染，移植和癌症在内的肝脏的免疫条件很重要。