Role of TH1 Cytokines in the Induction and Regulation of EAE

TH1 细胞因子在 EAE 诱导和调节中的作用

• 批准号: 7921428
• 负责人: VIJAY K. KUCHROO
• 金额: $ 30.61万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/7921428
• 关键词: Address; Affect; Allergic; Antibodies; Antigens; Attention; Autoimmune Diseases; Autoimmune Process; Autoimmunity; Binding; Biological Process; CD4 Positive T Lymphocytes; CNS autoimmune disease; Cell Differentiation process; Cell Surface Proteins; Cell surface; Cells; Chimeric Proteins; Collaborations; Cytokine Gene; Data; Demyelinations; Development; Disease; Disease remission; Dose; Encephalomyelitis; Experimental Autoimmune Encephalomyelitis; Extracellular Domain; Family; Family member; Gene Expression; Gene Family; Gene Proteins; Generations; Grant; Hand; Helper-Inducer T-Lymphocyte; Human; Immunoglobulins; Inflammatory; Injection of therapeutic agent; Interleukin-12; Interleukin-4; Kinetics; Length; Ligands; Lymphoid Cell; Mediating; Membrane; Messenger RNA; Methods; Molecular; Monoclonal Antibodies; Mucins; Multiple Sclerosis; Mus; Myelin; Myelogenous; Nature; Nose; Organ; Pathway interactions; Pattern; Peripheral; Phase; Phenotype; Phosphorylation; Play; Predisposition; Production; Proteins; RNA Splicing; Reagent; Regulation; Relapse; Remission Induction; Resistance; Role; Signal Transduction; Specificity; Surface; T-Cell Activation; T-Lymphocyte; Testing; Th2 Cells; Transcriptional Regulation; activating transcription factor; autoreactive T cell; base; cytokine; human disease; in vivo; interleukin-23; macrophage; member; novel; oral tolerance; programs; protein expression; receptor; response; tool; transcription factor

Accumulating evidence suggests that Thl that produce IFN-y and with specificity for myelin antigens are very potent in inducing the autoimmune disease of the CNS called experimental autoimmune encephalomyelitis (EAE). However, it has been difficult to differentiate autopathogenic Thl cells from other cells based on cell surface phenotype. Since Thl have been traditionally identified by the cytokines that they produce, it became important to identify cell surface molecules that can differentiate these cells. We have recently identified a novel gene family called TIM (T cell, Immunoglobulin and Mucin containing) that encodes cell surface molecules expressed on differentiated T cells. Whereas Tim-3 is expressed on the surface of differentiated Thl cells, our preliminary data suggests that another family member Tim-2 is expressed on Th2 cells. In addition, we have recently discovered an alternatively spliced, soluble form of Tim-3. The kinetics of expression of the soluble Tim-3 molecule during Thl differentiation is not known and its biological function has never been studied. We hypothesize that the function of Tim molecules may be to regulate expansion and effector functions of effector Th cells. This is supported by the observations that soluble fusion protein of Tim-3 (Tim-3Ig) was found to abrogate development of high dose tolerance and enhance Thl responses and EAE. In contrast, Tim2Ig fusion protein was found to inhibit development of EAE. The mechanism by which Tim-3Ig abrogate tolerance and enhance EAE and Tim2Ig fusion proteins protect mice from developing EAE is not understood. In this grant we propose to a) study the kinetics of expression of soluble Tim-3 and nature of cytokines and transcription factors that regulate expression of Tim2 and Tim3 on the T cell surface; b) study the kinetics of expression of Tim-2 protein on the surface of Th2 cells and determine the mechanism by which Tim2Ig inhibits development of EAE; and c) analyze whether Tim-3Ig fusion will also abrogate oral tolerance like the high dose tolerance and define the cellular mechanisms by which Tim-3Ig inhibits tolerance induction. These studies will provide fundamental information on the cellular and molecular mechanisms by which IFN-y and Thl cells play a role in the induction of EAE. Furthermore, these studies will define how the Tim family of molecules particularly Tim-2 and Tim-3 may be involved in the effector functions of the pathogenic autoreactive T cell responses and how blocking Tim pathway in vivo may alter the course of the CNS autoimmune disease, EAE.

积累的证据表明，产生IFN-Y且具有特异性的髓磷脂抗原的TH非常非常 有效诱导中枢神经系统的自身免疫性疾病，称为实验性自身免疫性脑脊髓炎（EAE）。 但是，很难根据细胞表面区分自动性THL细胞与其他细胞 表型。由于传统上是由它们产生的细胞因子鉴定的，因此很重要 鉴定可以区分这些细胞的细胞表面分子。我们最近确定了一个新型的基因家族称为 Tim（T细胞，免疫球蛋白和粘蛋白），编码在分化T中表达的细胞表面分子 细胞。 tim-3在分化的THL细胞的表面表达，而我们的初步数据表明另一个 家庭成员Tim-2在Th2细胞上表达。此外，我们最近发现了一个剪接的， TIM-3的可溶形式。 THL分化过程中可溶性TIM-3分子表达的动力学不是 已知及其生物学功能从未被研究过。我们假设Tim分子的功能可能是 调节效应子Th细胞的膨胀和效应函数。这是可溶的观察结果支持的 发现TIM-3（TIM-3ig）的融合蛋白消除了高剂量耐受性的发展并增强了Thl 回应和伊斯兰教。相反，发现Tim2ig融合蛋白抑制EAE的发展。机制 tim-3ig消除了耐受性并增强EAE和Tim2ig Fusion蛋白保护小鼠免受EAE的发展 不理解。 在这项赠款中，我们建议a）研究可溶性Tim-3和细胞因子性质的表达动力学和 调节TIM2和TIM3在T细胞表面表达的转录因子； b）研究表达的动力学 TIM-2蛋白在Th2细胞表面的 伊c）分析tim-3ig融合是否也将消除口服耐受性，例如高剂量耐受性并定义 TIM-3Ig抑制耐受性诱导的细胞机制。 这些研究将提供有关IFN-Y和IFN-Y和分子机制的基本信息 THL细胞在EAE的诱导中起作用。此外，这些研究将定义蒂姆分子家族如何 特别是TIM-2和TIM-3可能参与致病性T细胞反应的效应子功能 以及在体内阻塞tim途径如何改变CNS自身免疫性疾病的过程，EAE。