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: 8084129
• 负责人: SCOTT S ZAMVIL
• 金额: $ 27.03万
• 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/8084129
• 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; Health; 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; Principal Investigator; 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; 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. PUBLIC HEALTH RELEVANCE: Recent research has demonstrated that glatiramer acetate (GA, Copolymer-1, Copaxone(r)), an approved therapy for multiple sclerosis (MS), induces anti-inflammatory "type II" antigen presenting cells (APC) that are responsible for T cell immune modulation, providing a new understanding how GA functions in MS treatment. In this research program, we will elucidate the mechanisms responsible for induction of type II anti-inflammatory monocytes in mice and in GA-treated patients and determine how these regulatory APC influence T cell regulation. These studies should 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，共聚物-1，Copaxone（r））治疗多发性硬化（MS）患者与GA反应性Th 2和CD 4 + CD 25+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，使其分泌抗炎的“II型”细胞因子。我们研究了GA处理如何改变单核细胞活性以及这些APC如何影响T细胞活化。GA处理小鼠促进了“II型”单核细胞的发育，其特征在于IL-10和TGF-β分泌增加，TNF和IL-12分泌减少，以及STAT 1信号转导减少。II型单核细胞促进幼稚T（Th 0）细胞分化为Th 2和FoxP 3 + Treg，而不依赖于Ag特异性。II型单核细胞诱导的调节性T细胞特异性的非自身抗原的连续转移改善EAE，表明与髓鞘抗原的交叉反应性，被认为是T细胞介导的免疫调节GA的先决条件，是不需要的。将II型单核细胞连续转移到患有EAE的小鼠中可逆转瘫痪，抑制Th 17细胞发育并促进Th 2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靶标。我们还建立了这种新的范式，过继转移调节单核细胞，可用于研究APC-T细胞在体内的相互作用。我们建议研究通过GA处理参与单核细胞II型分化的途径，并表征II型单核细胞如何在体内诱导Th 2细胞和Treg。我们推测，除了STAT 1，其他信号通路，特别是STAT 3和NF-？B，可能在II型单核细胞中发生改变。我们推测，TGF-2的表达II型单核细胞是必要的，这些细胞在体内诱导调节性T细胞。具体而言，我们提出，（1）评估体内II型单核细胞的特性，并表征其诱导Treg和Th 2细胞的需求。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持多久。通过过继转移IL-10缺陷型或TGF-β缺陷型“II型单核细胞”，我们将确定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型单核细胞是否诱导适应性或天然Treg细胞。(2)分子途径（如NF-？B和MAPK），其可能参与II型单核细胞分化。(3)与我们的鼠研究平行，我们将评估开始GA治疗的MS患者中II型单核细胞的发育，并解决II型单核细胞是否可能在这些患者中发育参与调节性T细胞的诱导。我们提出的研究与MS治疗高度相关，因为它们可以提供洞察力，从而开发可以比GA更有效地促进II型APC分化和T细胞免疫调节的试剂。 公共卫生相关性：最近的研究表明，醋酸格拉替雷（GA，共聚物-1，Copaxone（r）），一种批准的治疗多发性硬化症（MS），诱导抗炎的“II型”抗原呈递细胞（APC），负责T细胞免疫调节，提供了一个新的理解GA如何在MS治疗中发挥作用。在这项研究计划中，我们将阐明负责诱导小鼠和GA治疗患者的II型抗炎单核细胞的机制，并确定这些调节APC如何影响T细胞调节。这些研究应该提供洞察力，导致开发的试剂，可以促进II型APC分化和T细胞免疫调节比GA更有效。