IL-12/IL-23 in Intravenous Tolerance

IL-12/IL-23 静脉耐受性

• 批准号: 6758980
• 负责人: A.M. Rostami
• 金额: $ 32.68万
• 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/6758980
• 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）：通过施用自身抗原诱导抗原特异性耐受是实验性过敏性脑脊髓炎（EAE）的有效免疫疗法，EAE是中枢神经系统炎症性脱髓鞘的模型。耐受诱导的机制可能包括克隆缺失、无反应性和诱导 T 辅助细胞 1 (Th1) 向 Th2 表型转变。 IL-12p40、IL-12 和 IL-23 的异二聚体是由激活的抗原呈递细胞 (APC) 产生的促炎细胞因子。它们具有驱动 Th1 分化和/或 Th1 克隆扩增的能力。 我们和其他人已经证明，通过静脉内 (i.v.) 耐受来抑制 EAE 与 IL-12 的下调相关，并且 IL-12 的施用会阻断耐受的诱导。然而，这种现象背后的机制尚不清楚。耐受性对 IL-23、IL-12/IL-23 受体及其信号转导途径调节的影响尚不清楚。目前尚不清楚 IL-12/IL-23 对 APC 功能有何影响（如果有），APC 可能在通过 Th1 向 Th2 转变诱导耐受中发挥重要作用。 在本项目中，我们将比较和对比 IL-12 和 IL-23 在 EAE 耐受中的作用。具体来说，我们将测试以下假设：1) i.v.施用自身抗原导致 APC2 的产生和 IL-12/IL-23 的下调。反过来，在耐受的 EAE 小鼠中，这会将 Th1 转变为 Th2 表型； 2) IL-23 在预防和消除已建立的耐受性方面发挥着关键作用。为了检验这些假设，我们提出以下具体目标：1）比较和对比 IL-12 和 IL-23 在预防诱导或废除已建立的静脉注射中的作用。 EAE 耐受性； 2）研究静脉注射的机制。 EAE 中 IL-12/IL-23 和 APC 功能的耐受诱导调节； 3) 研究静脉注射的效果。 EAE 中 IL-12 和 IL-23 受体的耐受性及其信号转导途径。从这些研究中获得的信息应该有助于确定静脉注射的机制。耐受性并为中枢神经系统炎症脱髓鞘的特异性免疫疗法铺平道路。