Role of S1P1 in the function of Regulatory T cells in Autoimmune Encephalomyeliti

S1P1 在自身免疫性脑脊髓炎调节性 T 细胞功能中的作用

• 批准号: 8889765
• 负责人: Mohamed Oukka
• 金额: $ 48.5万
• 依托单位: SEATTLE CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2015-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8889765
• 关键词: Address; Adverse effects; Affect; Agonist; Attention; Autoimmune Diseases; Autoimmune Process; Autoimmunity; B-Lymphocytes; Blood Circulation; CD4 Positive T Lymphocytes; Cells; Data; Development; Disease; Endothelial Cells; Experimental Autoimmune Encephalomyelitis; Generations; Health; Human; IL2RA gene; Immune; Immune response; Immune system; Immunosuppressive Agents; In Vitro; Inflammation; Interferons; Interleukin-10; Lesion; Lipids; Lymphocyte; Lymphoid; Lymphoid Tissue; Maintenance; Mediating; Molecular; Mouse Strains; Multiple Sclerosis; Mus; Neuraxis; Oral; Organ; Patients; Peripheral; Pharmaceutical Preparations; Play; Population; Positioning Attribute; Regulation; Regulatory T-Lymphocyte; Relapse; Role; Second Messenger Systems; Self Tolerance; Signal Transduction; Sphingosine-1-Phosphate Receptor; Spleen; T-Lymphocyte; Testing; Thymectomy; Thymus Gland; Time; Tissues; Transforming Growth Factor beta; analog; base; in vivo; interest; lymph nodes; migration; nervous system development; novel; overexpression; second messenger; sphingosine 1-phosphate; trafficking

DESCRIPTION (provided by applicant): Recently, S1P and S1P receptors have been specifically targeted as treatments for immune-mediated diseases, particularly the immunosuppressant FTY720 (Fingolimod Gilenya), an S1P analogue that has recently become the first oral therapy for relapsing Multiple Sclerosis. FTY720 effectively decreases relapse rates better than interferon β therapy; however, a subset of patients treated with FTY720 develop very severe relapses and even tumorfactive lesions. This finding suggests that S1P1-mediated signaling may be involved in some unknown immune regulation, in addition to its role in T and B cell trafficking. Although it remains controversial whether FTY720, after being phosphorylated to FTY720-P in vivo, acts as an agonist or a functional antagonist, understanding how FTY720 affects the function of T regulatory cells (Tregs) is crucial for limiting the adverse effects of lng term therapy with this drug. In order to address the specific role of S1P on Tregs, we have generated mice that lack S1P1 only in Tregs. We have found 10 times more Tregs in the thymus of S1P1 Treg-deficient mice compared to WT mice In the periphery however, we have found that S1P1 is not required for the egress of Tregs from lymph nodes or their tissue trafficking. Tregs that lack S1P1 could still suppress in vitro and expressed normal levels of IL-10, TGF beta, CD25 and CTL4; however, these Tregs lost their ability to control immune responses in vivo. Indeed, S1P1 Treg-deficient mice developed rapid and severe systemic autoimmunity, revealing a critical role of S1P for the function of Treg. Thus, from our preliminary data we hypothesize that S1P1-mediated signaling is: 1) crucial for the egress of Tregs from the thymus, 2) crucial for the fine positioning of Tregs within lymphoid organs and 3) crucial for the suppression function of Tregs in tissues such as the CNS. Whereas S1P1-mediated signaling is required for T cell egress and trafficking, S1P1 may control the functions of Tregs differently. To address these hypotheses, we propose to carry out the following specific aims: Aim 1. Role of S1P1 in the generation of Tregs in the Thymus Aim 2. Investigate whether compromised S1P1 expression affects Treg positioning in secondary lymphoid tissues Aim 3. Determine the requirement of selective S1P1 for the migration of Treg cells in the CNS and the development of EAE. This novel mouse strain and new findings will help us understand how S1P and Fingolimod affect the function of Tregs during the course of Multiple Sclerosis.

描述（由申请人提供）：最近，S1 P和S1 P受体已被特异性靶向作为免疫介导的疾病的治疗，特别是免疫抑制剂FTY 720（Fingolimod Gilenya），这是一种S1 P类似物，最近已成为复发性多发性硬化症的第一种口服疗法。FTY 720有效降低复发率 然而，用FTY 720治疗的一部分患者发展为非常严重的复发，甚至肿瘤性病变。这一发现表明，S1 P1介导的信号可能涉及一些未知的免疫调节，除了它在T和B细胞运输的作用。虽然FTY 720在体内磷酸化为FTY 720-P后，是否作为激动剂或功能性拮抗剂仍存在争议，但了解FTY 720如何影响T调节细胞（TCFs）的功能对于限制使用该药物的短期治疗的不良反应至关重要。为了解决S1 P对Tcb的特定作用，我们已经产生了仅在Tcb中缺乏S1 P1的小鼠。我们已经发现，与WT小鼠相比，S1 P1 Treg缺陷小鼠的胸腺中的TlR多10倍。然而，我们发现，S1 P1不是TlR从淋巴结或其组织运输中排出所必需的。缺乏S1 P1的TCLs在体外仍然可以抑制IL-10、TGF β、CD 25和CTL 4的表达，并且表达正常水平;然而，这些TCLs失去了它们在体内控制免疫应答的能力。事实上，S1 P1 Treg缺陷小鼠产生了快速和严重的全身性自身免疫，揭示了S1 P对Treg功能的关键作用。因此，从我们的初步 根据这些数据，我们假设S1 P1介导的信号传导是：1）对于胸腺素从胸腺的排出至关重要，2）对于胸腺素在淋巴器官内的精细定位至关重要，和3）对于胸腺素在组织如CNS中的抑制功能至关重要。尽管S1 P1介导的信号传导是T细胞外出和运输所必需的，但S1 P1可能以不同的方式控制T细胞的功能。到 为了解决这些假设，我们建议实现以下具体目标：目标1。S1 P1在胸腺Aim 2中调节性T细胞生成中的作用。研究受损的S1 P1表达是否影响次级淋巴组织中Treg的定位目的3。确定CNS中Treg细胞迁移和EAE发生对选择性S1 P1的需求。这种新的小鼠品系和新的发现将帮助我们了解S1 P和Fingolimod如何在多发性硬化症过程中影响Tclad的功能。