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

描述（由申请人提供）： 虽然慢性环孢素或 基于FK506 免疫抑制显著改善了器官移植 存活，绝大多数患者发展为移植物功能受损或 甚至由于慢性排斥而导致移植失败。因此，最终目标- 从根本上提高移植物存活率-必须通过诱导 器官移植耐受，无需持续药物治疗。 我们的研究结果表明，设计的供体/受体组织相容性 蛋白质可以诱导耐受性。 宽容的接受者 表现出选择性 产生白细胞介素（IL）-4的Th2细胞的活化， 通过细胞内分子ERK 2、NF-κ B AP-1、Jak3和 Stat5.我们认为致耐受蛋白诱导耐受依赖于 用IL-4驱动的Jak3/Stat5/Stat6扩增独特的调节性Th2 反馈回路事实上，我们打算表明存在两种类型的Th2 细胞：即，调节性Th2与IL-4驱动的Stat5和Stat6以及经典的 Th2与IL-4驱动的Stat6，而不是Stat5。此外，我们计划展示 这些亚群受到Jak/Stat调节分子家族的调节， 包括细胞因子信号转导抑制因子（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SH 2 含蛋白（Shp）-1。 这项研究可能提供证据， 疫苗诱导有效的Jak/Stat调节蛋白，这有助于 耐受诱导

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.