Programming dendritic cells to induce tolerogenic response and suppress brain inf

对树突状细胞进行编程以诱导耐受反应并抑制大脑信息

• 批准号: 8716336
• 负责人: Santhakumar Manicassamy
• 金额: $ 35.25万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-15 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8716336
• 关键词: Adjuvant; Adoptive Transfer; Adverse effects; Antigen-Presenting Cells; Antigens; Autoantigens; Autoimmune Process; Biological; Biological Assay; Brain; Cell Differentiation process; Cells; Chronic; Clinical; Complex; Data; Decision Making; Dendritic Cells; Development; Disease; Encephalitis; Equilibrium; Experimental Autoimmune Encephalomyelitis; Family member; Genes; Genetic; Immune; Immune system; Immunology; Immunosuppression; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Interleukin-10; Interleukin-6; Intervention; Intestines; Knock-out; Mediating; Modeling; Molecular; Molecular Target; Multiple Sclerosis; Mus; Neurons; Pathologic; Pathway interactions; Phase; Phenotype; Play; Process; Property; Protein Isoforms; Regulator Genes; Regulatory T-Lymphocyte; Role; Severity of illness; Signal Pathway; Signal Transduction; Spinal Cord; Spleen; TCF Transcription Factor; TCF7L2 gene; TLR2 gene; Testing; Therapeutic; Transfection; cytokine; in vivo; in vivo Model; insight; interleukin-23; macrophage; novel; novel therapeutic intervention; pathogen; peripheral tolerance; prevent; programs; promoter; response; selective expression

DESCRIPTION (provided by applicant): Multiples Sclerosis (MS) is an important clinical problem, but molecular targets for antigen-specific therapeutic immune intervention remain elusive. The immune phenotype of MS is best mimicked in the experimental autoimmune encephalomyelitis (EAE) model in mice. Antigen presenting cells such as dendritic cells (DCs) play a pivotal role in mediating peripheral tolerance and suppressing inflammation. In EAE, these cells lose their tolerogenic properties resulting in uncontrolled neuronal inflammation. Current therapies involve non-specific immune suppression with long-term side effect and not just antigen specific suppression. We have shown recently that Wnt-¿-catenin pathway in dendritic cells and macrophages play critical role in modulating inflammatory responses in the intestine. Given that EAE is a chronic inflammatory disease, we sought to determine the function of Wnt-¿-catenin pathway in dendritic cells and macrophages in autoimmune brain inflammation. Now, we show that, functionally, the ¿-catenin/TCF signaling pathway plays a critical biological role in programming DCs and Macrophages to induce tolerogenic response and prevents brain inflammation. However, downstream mechanisms by which ¿-catenin/TCF pathway in DCs acts to create tolerance and prevents EAE are completely unknown. Our central hypothesis is that ¿-catenin/TCF transcription factors constitute a key molecular pathway in promoting regulatory phenotype in DCs that drives their ability to induce T regulatory cells (Tregs) differentiation and suppress Th1/Th17 cell differentiation. Together these are critical for promoting tolerance and suppressing EAE. We will test our hypothesis in the following specific aims (i) Test the hypothesis that ¿-catenin induced activation of the TCF transcription factor pathway is critical for the induction of two key immune regulatory genes - IL-10 and TGF-¿1 in response to adjuvant-induced EAE (Aim 1); (ii) Test the hypothesis that the ¿-catenin/TCF-4 pathway in DCs is critical for inducing MBP-specific T regulatory cells differentiation and suppressing pathological Th1/Th17 cell differentiation (Aim 2); (iii) Test the hypothesis that, functionally, the ¿-catenin/TCF pathway plays a critical biological role in inducing tolerogenic response and suppressing pathologic inflammatory response in the brain and spinal cord (Aim 3). The successful completion of the proposed studies will provide new mechanistic insights into how the ¿- catenin/TCF pathway in DCs and macrophages regulate a balance between tolerance and inflammatory responses, and will provide a mechanistic rationale for targeting this pathway in MS. Pharmacological activators of ¿-catenin pathway already exist, and more are in development. The proposed studies will provide a rationale for the development of an entirely new class of agents that may have significant therapeutic impact in treating MS.

描述（由申请人提供）：多发性硬化（MS）是一个重要的临床问题，但抗原特异性治疗性免疫干预的分子靶点仍然难以捉摸。MS的免疫表型在小鼠实验性自身免疫性脑脊髓炎（EAE）模型中得到最好的模拟。抗原呈递细胞如树突状细胞（DCs）在介导外周耐受和抑制炎症中起关键作用。在EAE中，这些细胞失去其致耐受性，导致不受控制的神经元炎症。目前的治疗涉及具有长期副作用的非特异性免疫抑制，而不仅仅是抗原特异性抑制。我们最近发现树突状细胞和巨噬细胞中的Wnt-β-连环蛋白通路在调节肠道炎症反应中起关键作用。鉴于EAE是一种慢性炎症性疾病，我们试图确定自身免疫性脑炎症中树突状细胞和巨噬细胞中Wnt-β-连环蛋白通路的功能。现在，我们表明，在功能上，连环蛋白/TCF信号通路在编程DC和巨噬细胞诱导耐受性反应和预防脑炎症中起着关键的生物学作用。然而，DCs中的连环蛋白/TCF通路产生耐受和预防EAE的下游机制完全未知。我们的中心假设是，连环蛋白/TCF转录因子构成了促进DC中调节表型的关键分子通路，其驱动DC诱导调节性T细胞（T细胞）分化和抑制Th 1/Th 17细胞分化的能力。这些因素合在一起， 促进耐受和抑制EAE。我们将在以下具体目标中检验我们的假设：（i）检验以下假设：在应答药物诱导的EAE时，连环蛋白诱导的TCF转录因子途径的激活对于诱导两个关键免疫调节基因- IL-10和TGF-β 1至关重要（目标1）;（ii）检验以下假设：DC中的-catenin/TCF-4通路对于诱导MBP特异性调节性T细胞分化和抑制病理性Th 1/Th 17细胞分化至关重要（Aim 2）;（iii）测试以下假设：β-连环蛋白/TCF通路在诱导脑和脊髓中的致耐受性应答和抑制病理性炎症应答中起关键的生物学作用（目的3）。拟议研究的成功完成将为DC和巨噬细胞中的<$- catenin/TCF通路如何调节耐受性和炎症反应之间的平衡提供新的机制见解，并将为MS中靶向该通路提供机制原理。<$-catenin通路的药理学激活剂已经存在，并且更多正在开发中。拟议的研究将为开发一种全新的药物提供理论基础，这种药物可能对治疗MS具有显著的治疗作用。