Regulation of IL-4/IL-4R Signaling Pathway Mediate Tole*

IL-4/IL-4R 信号通路介导调节*

• 批准号: 6528201
• 负责人: Stanislaw M Stepkowski
• 金额: $ 22.35万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCI CTR HOUSTON
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-09-01 至 2004-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6528201
• 关键词: biological signal transduction; cytokine receptors; graft versus host disease; helper T lymphocyte; immune tolerance /unresponsiveness; immunoregulation; interleukin 4; laboratory mouse; laboratory rat; major histocompatibility complex

DESCRIPTION (provided by applicant): Although chronic cyclosporine or FK506-based immunosuppression has dramatically improved organ allograft survival, the vast majority of patients develop impaired graft function or even graft failure owing to chronic rejection. Therefore, the ultimate goal - to radically improve graft survival -must be achieved by induction of tolerance of organ allografts without the need for continuous drug therapy. Our results have demonstrated that designed donor/recipient histocompatibility proteins may induce tolerance. Tolerant recipients exhibited selective activation of interleukin (IL)-4-producing Th2 cells, which displayed reduced signaling through the intracellular molecules ERK2, NF-kappaB AP-1, Jak3, and Stat5. We propose that tolerance induction by tolerogenic protein depends upon the expansion of a unique regulatory Th2 with an IL-4-driven Jak3/Stat5/Stat6 feedback loop. In fact, we intend to show the existence of two types of Th2 cells: namely, regulatory Th2 with IL-4-driven Stat5 and Stat6 and classical Th2 with IL-4-driven Stat6 but not Stat5. Furthermore, we plan to demonstrate that these subsets are modulated by a family of Jak/Stat regulatory molecules, including supressors of cytokine signaling (SOCS)-1, SOCS-2, SOCS-3, cytokine inducible SH-2 containing protein (CIS)-1, and tyrosine phosphatase SH2 containing protein (Shp)-1. This study may provide evidence that tolerogenic vaccines induce potent Jak/Stat regulatory proteins, which are instrumental in tolerance induction.

描述(由申请人提供)：虽然慢性环孢素A或 基于FK506的免疫抑制显著改善了同种异体器官移植 存活，绝大多数患者出现移植物功能受损或 甚至因慢性排斥而导致移植物失败。因此，最终的目标是- 从根本上提高移植物的存活率-必须通过诱导 不需要持续药物治疗的同种异体器官移植的耐受性。 我们的结果表明，设计的供受者组织相容性 蛋白质可以诱导耐受性。宽容的接受者表现出选择性 产生IL-4的Th2细胞活化，表现为减少 通过细胞内分子ERK2、NF-kappaB AP-1、JAK3和 统计数据5.我们认为，产生耐受的蛋白质诱导耐受依赖于 用IL-4驱动的JAK3/STAT5/STAT6扩展独特的调节性Th2 反馈环路。事实上，我们打算展示两种类型的Th2的存在 细胞：即通过IL-4驱动的Stat5和Stat6以及经典的调节性Th2 Th2与IL-4驱动的Stat6，而不是Stat5。此外，我们计划演示 这些亚群受到一系列Jak/Stat调节分子的调节， 包括细胞因子信号转导抑制物(SOCS)-1、SOCS-2、SOCS-3、细胞因子 含诱导SH-2蛋白(CIS)-1和酪氨酸磷酸酶SH2 含蛋白质(SHP)-1。这项研究可能会提供证据，证明耐受性 疫苗诱导有效的JAK/STAT调节蛋白，这些蛋白在 耐受性诱导。