Regulatory monocytes in CNS autoimmune disease

中枢神经系统自身免疫性疾病中的调节性单核细胞

• 批准号: 8487462
• 负责人: SCOTT S ZAMVIL
• 金额: $ 26.08万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8487462
• 关键词: Address; Adenosine; Adoptive Transfer; Anti-Inflammatory Agents; Anti-inflammatory; Antigen-Presenting Cells; Antigens; Autoantigens; CNS autoimmune disease; Cell Communication; Cells; Complement Factor B; Copaxone; Development; Experimental Autoimmune Encephalomyelitis; Genes; Goals; IL2RA gene; Interleukin-10; Interleukin-12; Lead; MAP2K3 gene; Mediating; Mitogen-Activated Protein Kinases; Molecular; Multiple Sclerosis; Mus; Myelin; Myelogenous; Nuclear; Paralysed; Pathway interactions; Patient Monitoring; Patients; Phosphotransferases; Property; Proteins; Reagent; Regulation; Regulatory T-Lymphocyte; Relative (related person); Reporter; Reporting; Research; Role; STAT1 protein; STAT3 gene; Second Messenger Systems; Signal Pathway; Signal Transduction; Specificity; T cell differentiation; T cell regulation; T-Cell Activation; T-Lymphocyte; TNF gene; Testing; Th2 Cells; Time; Wild Type Mouse; copolymer 1; cross reactivity; cytokine; immunoregulation; in vivo; insight; monocyte; novel; programs; public health relevance; response; second messenger

DESCRIPTION (provided by applicant): Treatment of multiple sclerosis (MS) patients with glatiramer acetate (GA, Copolymer-1, Copaxone(r)) has been associated with induction of GA-reactive Th2 and CD4+CD25+ regulatory T cells (Treg). Research indicates that GA also exerts immunomodulatory activity on antigen (Ag) presenting cells (APC), causing them to secrete an anti-inflammatory "type II" cytokines. We investigated how GA treatment alters monocyte activity and how these APC influence T cell activation. GA treatment of mice promoted development of "type II" monocytes, which were characterized by increased secretion of IL-10 and TGF-¿, reduced secretion of TNF and IL-12, and reduced STAT1 signaling. Type II monocytes promoted differentiation of na¿ve T (Th0) cells into Th2 and FoxP3+ Treg independent of Ag specificity. Adoptive transfer of type II monocyte-induced regulatory T cells specific for a non-self Ag ameliorated EAE, indicating that cross-reactivity with myelin Ag, considered a prerequisite for T cell-mediated immune modulation by GA, is not required. Adoptive transfer of type II monocytes into mice with EAE reversed paralysis, suppressed Th17 cell development and promoted both Th2 differentiation and expansion of Treg. These findings indicate that APC are a primary target for GA- mediated immune modulation. We have also established how this novel paradigm, adoptive transfer of regulatory monocytes, can be used to study APC-T cell interaction in vivo. We propose to investigate the pathway(s) involved in type II differentiation of monocytes by GA treatment and to characterize how type II monocytes lead to induction of Th2 cells and Treg in vivo. We hypothesize that, in addition to STAT1, other signaling pathways, in particular STAT3 and NF-?B, may be altered in type II monocytes. We hypothesize that expression of TGF-2 by type II monocytes is necessary for these cells to induce regulatory T cells in vivo. Specifically, we propose, (1) to evaluate properties of type II monocytes in vivo and characterize their requirements for induction of Treg and Th2 cells. We will determine type II monocytes survival and how long they retain their capability to induce immune modulation in recipient mice. By adoptive transfer of IL-10-deficient or TGF-¿-deficient "type II monocytes" we will establish the relative contribution of these cytokines for induction of regulatory T cells by monocytes. We will evaluate whether type II monocytes induce adaptive or natural Treg cells. (2) Molecular pathways (e.g. NF-?B and MAPK) that may be involved in type II monocyte differentiation will be examined. (3) In parallel with our murine studies, we will evaluate type II monocyte development in MS patients that initiate GA treatment and address whether type II monocytes 5hat may develop in these patients participate in the induction of regulatory T cells. Our proposed studies are highly relevant to MS therapy as they may provide insight leading to the development of reagents that may promote type II APC differentiation and T cell immune modulation more effectively than GA.

描述（由申请人提供）：用醋酸格拉替雷（GA、Copolymer-1、Copaxone(r)）治疗多发性硬化症 (MS) 患者与诱导 GA 反应性 Th2 和 CD4+CD25+ 调节性 T 细胞 (Treg) 相关。研究表明，GA 还对抗原 (Ag) 呈递细胞 (APC) 发挥免疫调节活性，使它们分泌抗炎“II 型”细胞因子。我们研究了 GA 治疗如何改变单核细胞活性以及这些 APC 如何影响 T 细胞激活。 GA治疗小鼠促进了“II型”单核细胞的发育，其特征是IL-10和TGF-β的分泌增加、TNF和IL-12的分泌减少以及STAT1信号传导减少。 II 型单核细胞促进幼稚 T (Th0) 细胞分化为 Th2 和 FoxP3+ Treg，与 Ag 特异性无关。对非自体 Ag 特异性的 II 型单核细胞诱导的调节性 T 细胞的过继转移可改善 EAE，这表明不需要与髓磷脂 Ag 发生交叉反应，而髓磷脂 Ag 被认为是 GA 介导的 T 细胞介导的免疫调节的先决条件。将 II 型单核细胞过继转移至 EAE 小鼠体内可逆转麻痹，抑制 Th17 细胞发育并促进 Th2 分化和 Treg 扩增。这些发现表明 APC 是 GA 介导的免疫调节的主要目标。我们还建立了如何使用调节性单核细胞的过继转移这一新范例来研究体内 APC-T 细胞相互作用。我们建议通过 GA 处理研究单核细胞 II 型分化所涉及的途径，并表征 II 型单核细胞如何在体内诱导 Th2 细胞和 Treg。我们假设，除了 STAT1 之外，其他信号通路，特别是 STAT3 和 NF-κB，可能在 II 型单核细胞中发生改变。我们假设 II 型单核细胞表达 TGF-2 对于这些细胞在体内诱导调节性 T 细胞是必要的。具体来说，我们建议，(1) 评估 II 型单核细胞的体内特性并表征其诱导 Treg 和 Th2 细胞的要求。我们将确定 II 型单核细胞的存活率以及它们在受体小鼠中诱导免疫调节的能力保留多长时间。通过IL-10缺陷或TGF-β缺陷“II型单核细胞”的过继转移，我们将确定这些细胞因子对于单核细胞诱导调节性T细胞的相对贡献。我们将评估 II 型单核细胞是否诱导适应性或天然 Treg 细胞。 (2)检查可能参与II型单核细胞分化的分子途径（例如NF-κB和MAPK）。 (3) 与我们的小鼠研究并行，我们将评估开始 GA 治疗的 MS 患者中 II 型单核细胞的发育，并探讨这些患者中 II 型单核细胞 5hat 是否可能参与调节性 T 细胞的诱导。我们提出的研究与 MS 治疗高度相关，因为它们可能为开发比 GA 更有效地促进 II 型 APC 分化和 T 细胞免疫调节的试剂提供见解。