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

基本信息

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
项目类别：
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

项目摘要

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）：多发性硬化症（MS）是一个重要的临床问题，但抗原特异性免疫治疗干预的分子靶点仍然难以捉摸。多发性硬化症的免疫表型最好在小鼠实验性自身免疫性脑脊髓炎（EAE）模型中模拟。树突状细胞 (DC) 等抗原呈递细胞在介导外周耐受和抑制炎症方面发挥着关键作用，在 EAE 中，这些细胞失去其耐受性，导致不受控制。目前的疗法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。树突状细胞和巨噬细胞中的连环蛋白途径在调节肠道炎症反应中发挥着关键作用鉴于 EAE 是一种慢性炎症性疾病，我们试图确定 Wnt-¿自身免疫性脑炎症中树突状细胞和巨噬细胞中的连环蛋白途径现在，我们表明，在功能上， ¿ -连环蛋白/TCF信号通路在对DC和巨噬细胞进行编程以诱导耐受性反应并预防脑炎症方面发挥着关键的生物学作用。 DC 中的连环蛋白/TCF 通路可产生耐受性并预防 EAE，我们的中心假设是 ¿ -catenin/TCF 转录因子构成了促进 DC 调节表型的关键分子途径，可驱动 DC 诱导 T 调节细胞 (Treg) 分化和抑制 Th1/Th17 细胞分化的能力。促进耐受性并抑制 EAE 我们将在以下具体目标中检验我们的假设 (i) 检验假设 ¿ - 连环蛋白诱导的 TCF 转录因子通路激活对于诱导两个关键免疫调节基因 - IL-10 和 TGF-¿ 1 响应佐剂诱导的 EAE（目标 1）； (ii) 检验 ¿ - DC 中的连环蛋白/TCF-4 通路对于诱导 MBP 特异性 T 调节细胞分化和抑制病理性 Th1/Th17 细胞分化至关重要（目标 2）；（iii）从功能上检验 ¿ -连环蛋白/TCF 通路在诱导耐受性反应和抑制大脑和脊髓的病理性炎症反应中发挥着关键的生物学作用（目标 3）。拟议研究的成功完成将为了解 ¿ - DC 和巨噬细胞中的连环蛋白/TCF 通路调节耐受性和炎症反应之间的平衡，并将为 MS 的药理学激活剂靶向该通路提供机制原理。 -连环蛋白途径已经存在，并且更多的研究正在开发中，将为开发可能对治疗多发性硬化症具有显着治疗作用的全新药物类别提供依据。