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（由适用提供）：多发性硬化症（MS）患者乙酸盐（GA，共聚物1，Copaxone（R））与GA反应性TH2和CD4+ CD25+调节性T细胞（TREG）的诱导有关。研究表明，GA还对抗原（Ag）呈递细胞（APC）发挥免疫调节活性，从而导致它们秘密秘密抗炎“ 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。小鼠的GA处理促进了“ II型”单核细胞的发育，其特征在于IL-10和TGF- - 分泌增加，TNF和IL-12的分泌减少以及STAT1信号传导降低。 II型单核细胞促进了NA¿T（Th0）细胞分化为Th2和Foxp3+ Treg，独立于Ag特异性。对非自身AG改善EAE的II型单核细胞诱导的调节T细胞的过继转移，表明与髓磷脂AG的交叉反应性被认为是通过GA进行T细胞介导的免疫调节的先决条件。 II型单核细胞的收养转移到EAE逆转的小鼠中，抑制了Th17细胞的发育，并促进了TH2分化和Treg的扩张。这些发现表明APC是GA-介导的免疫调节的主要目标。我们还建立了这种新颖的范式如何使用调节单核细胞的自适应转移，可用于研究体内的APC-T细胞相互作用。我们建议通过GA处理研究与单核细胞II型分化有关的途径，并表征II型单核细胞如何导致Th2细胞和Treg在体内诱导。我们假设除STAT1外，其他信号通路（尤其是STAT3和NF-？b）可能会在II型单核细胞中改变。我们假设通过II型单核细胞表达TGF-2对于这些细胞在体内诱导调节T细胞是必要的。具体而言，我们建议（1）评估体内II型单核细胞的性质，并表征其诱导Treg和Th2细胞的要求。我们将确定II型单核细胞的存活以及它们保留其诱导受体小鼠免疫调节能力的时间。通过自适应转移IL-10缺陷型或TGF-缺陷型“ II型单核细胞”，我们将建立这些细胞因子对单核细胞诱导调节性T细胞的相对贡献。我们将评估II型单核细胞是诱导适应性或天然Treg细胞。 （2）将检查可能与II型单核细胞分化有关的分子途径（例如NF-？B和MAPK）。 （3）与我们的鼠研究同时，我们将评估MS患者II型单核细胞发育的启动GA治疗，并解决这些患者的II型单核细胞5HAT是否可能出现5HAT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，因为它们可能会提供洞察力，从而导致可能比GA更有效地促进II型APC分化和T细胞免疫调节的试剂的发展。