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（由应用提供）：多发性硬化症（MS）是一个重要的临床问题，但是抗原特异性治疗免疫学干预的分子靶标仍然难以捉摸。在小鼠的实验性自身免疫性脑脊髓炎（EAE）模型中，最好模仿MS的免疫学表型。抗原呈现的细胞（例如树突状细胞（DC））在介导外周耐受性和抑制注射中起关键作用。在EAE中，这些细胞失去了其耐受性特性，导致神经元炎症不受控制。当前的疗法涉及非特异性免疫抑制，并具有长期副作用，而不仅仅是抗原特异性抑制。我们最近表明，树突状细胞和巨噬细胞中的Wnt -�-蛋白素途径在调节肠中的炎症反应中起着至关重要的作用。鉴于EAE是一种慢性炎症性疾病，我们感觉到确定Wnt -�-蛋白磷酸途径在树突状细胞和自身免疫性脑感染中巨噬细胞中的功能。现在，我们表明，从功能上讲， - 帕宁蛋白/TCF信号通路在编程DC和巨噬细胞中起着至关重要的生物学作用，可诱导耐受性反应并防止脑感染。但是，DCS中的-Catenin/TCF途径的下游机制可以创造公差并防止EAE完全未知。我们的中心假设是 - - 蛋白蛋白/TCF转录因子构成了促进DC中调节表型的关键分子途径，该途径驱动其诱导T调节细胞（Tregs）分化的能力并抑制TH1/TH17细胞分化。在一起对 促进耐受性和抑制EAE。我们将在以下特定目的（i）测试以下假设的假设： - 帕宁蛋白诱导的TCF转录因子途径的激活对于诱导两个关键的免疫调节基因-IL-10和TGF-€1响应调整诱导的EAE时，TCF转录因子途径的激活至关重要（AIM 1）； （ii）检验了DC中的 - 帕宁/TCF-4途径的假设对于诱导MBP特异性T调节细胞分化和抑制病理TH1/TH17细胞分化至关重要（AIM 2）； （iii）检验以下假设：从功能上讲，� -catenin/tcf途径在诱导的耐受性反应和抑制大脑和脊髓的病理炎症反应中起着至关重要的生物学作用（AIM 3）。拟议的研究的成功完成将为DC和巨噬细胞中的catenin/TCF途径如何提供新的机械见解，从而调节耐受性和炎症反应之间的平衡，并为靶向MS中的该途径提供机械基础。 �-帕宁蛋白途径的药理学激活剂已经存在，并且正在开发中。拟议的研究将为开发一类全新的药物的发展提供理由，这些药物可能在治疗MS方面具有重大的热影响。