Role of IL-12/IL-23 in Intravenous Tolerance

IL-12/IL-23 在静脉耐受中的作用

• 批准号: 7105472
• 负责人: A.M. Rostami
• 金额: --
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-07-01 至 2009-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7105472
• 关键词: RNase protection assay; T lymphocyte; antigen presenting cell; apoptosis; autoantigens; biological signal transduction; cell differentiation; cytokine receptors; experimental allergic encephalomyelitis; flow cytometry; genetically modified animals; immune tolerance /unresponsiveness; interleukin 12; intravenous administration; laboratory mouse; receptor expression; transcription factor

DESCRIPTION (provided by applicant): Induction of antigen-specific tolerance by administration of the autoantigen is an effective immunotherapy for experimental allergic encephalomyelitis (EAE), a model for inflammatory demyelination of the central nervous system. The mechanisms underlying tolerance induction may include clonal deletion, anergy, and induction of a T-helper1 (Th1) to Th2 phenotype shift. Heterodimers of IL-12p40, IL-12 and IL-23, are proinflammatory cytokines produced by activated antigen-presenting cells (APCs). They have the capacity to drive Th1 differentiation and/or Th1 clonal expansion. We and others have shown that suppression of EAE by intravenous (i.v.) tolerance is associated with downregulation of IL-12, and administration of IL-12 blocks the induction of tolerance. However, mechanisms underlying this phenomenon are not clear. The effect of tolerance on the regulation of IL-23, IL-12/IL-23 receptors, and their signal transduction pathways is not known. Neither is it clear what effect, if any, IL-12/IL-23 have on the function of APCs, which may play a significant role in inducing tolerance through a Th1 to Th2 shift. In this project we will compare and contrast the role of IL-12 and IL-23 in EAE tolerance. Specifically, we will test the hypotheses that 1) i.v. administration of autoantigen results in the generation of APC2 and downregulation of IL-12/IL-23. This, in turn, shifts Th1 towards a Th2 phenotype in tolerized EAE mice; and 2) IL-23 plays a key role in prevention and abrogation of established tolerance. To test these hypotheses, we propose the following Specific Aims: 1) To compare and contrast the role of IL-12 and IL-23 in prevention of induction or abrogation of established i.v. tolerance in EAE; 2) To study the mechanisms of i.v. tolerance-induced regulation of IL-12/IL-23 and APC function in EAE; and 3) To study the effect of i.v. tolerance on the receptors for IL-12 and IL-23 and their signal transduction pathways in EAE. The information gained from these studies should help in defining the mechanisms of i.v. tolerance and pave the way for specific immunotherapies for CNS inflammatory demyelination.

描述（由申请人提供）：通过施用自身抗原的诱导抗原特异性耐受性是实验性过敏性脑脊髓炎（EAE）的有效免疫疗法，这是中枢神经系统炎症性脱髓鞘模型。诱导耐受性的基础机制可能包括克隆缺失，反应和T-Helper1（Th1）诱导到Th2表型转移。 IL-12P40，IL-12和IL-23的异二聚体是由活化的抗原呈递细胞（APC）产生的促炎细胞因子。它们具有驱动Th1分化和/或Th1克隆扩展的能力。 我们和其他人表明，通过静脉内（i.v.）耐受性抑制EAE与IL-12的下调有关，而IL-12的给药阻止了耐受性的诱导。但是，这种现象背后的机制尚不清楚。差异对IL-23，IL-12/IL-23受体的调节及其信号转导途径的调节的影响尚不清楚。也不清楚IL-12/IL-23对APC的功能有什么影响，这可能在通过TH1转移到Th2偏移的耐受性中起重要作用。 在这个项目中，我们将比较和对比IL-12和IL-23在EAE耐受性中的作用。具体而言，我们将测试1）i.v.的假设。自身抗原的给药会导致APC2产生和IL-12/IL-23的下调。反过来，这将TH1转移到了耐受的EAE小鼠中的Th2表型。 2）IL-23在预防和废除既定耐受性方面起着关键作用。为了检验这些假设，我们提出了以下具体目的：1）比较和对比IL-12和IL-23在预防已建立i.v.的诱导或废除方面的作用。在伊斯兰教中的宽容； 2）研究i.v.的机制EAE中耐受性诱导的IL-12/IL-23和APC功能的调节； 3）研究i.v.的影响IL-12和IL-23受体的耐受性及其在EAE中的信号转导途径。从这些研究中获得的信息应有助于定义静脉注射的机制。耐受性并为中枢神经系统炎症性脱髓鞘的特定免疫疗法铺平了道路。