Programming dendritic cells to induce tolerogenic response and suppress brain inf

描述(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。在实验性自身免疫性脑脊髓炎(EAE)小鼠模型中，MS的免疫表型最接近。树突状细胞(DC)等抗原提呈细胞在介导外周免疫耐受和抑制炎症方面发挥着关键作用。在EAE中，这些细胞失去耐受性，导致不受控制的神经细胞炎症。目前的治疗方法包括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-catenin通路在调节肠道炎症反应中起着关键作用。鉴于EAE是一种慢性炎症性疾病，我们试图确定树突状细胞和巨噬细胞中Wnt-β-catenin通路在自身免疫性脑炎症中的作用。现在，我们证明，从功能上讲，连环蛋白/TCF信号通路在编程DC和巨噬细胞诱导耐受反应和预防脑部炎症方面发挥着关键的生物学作用。然而，树突状细胞中-连环蛋白/TCF通路的下游机制是如何产生耐受和预防EAE的，目前还完全不清楚。我们的中心假设是-连环蛋白/TCF转录因子是促进树突状细胞调节表型的关键分子途径，从而驱动树突状细胞诱导T调节细胞(Tregs)分化和抑制Th1/Th17细胞分化。这些因素加在一起对 促进宽容，抑制EAE。我们将在以下特定目标检验我们的假设：(I)检验假设，即β-catenin诱导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-β1应答佐剂诱导的EAE至关重要(目标1)；(Ii)检验DC中β-catenin/TCF-4途径对于诱导MBP特异性T调节细胞分化和抑制病理性Th1/Th17细胞分化至关重要的假设(目标2)；(3)验证以下假设：在功能上，连环蛋白/TCF通路在诱导脑和脊髓的耐受性反应和抑制病理性炎症反应方面起着关键的生物学作用(目标3)。拟议研究的成功完成将为DC和巨噬细胞中？-catenin/TCF途径如何调节耐受和炎症反应之间的平衡提供新的机械学见解，并将为在MS中靶向这一途径提供机制基础。拟议的研究将为开发一类全新的药物提供理论基础，这些药物可能在治疗多发性硬化症方面具有显著的治疗效果。

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.