Modulation of Inflammatory Responses by Helminth Glycans

蠕虫聚糖调节炎症反应

• 批准号: 8900161
• 负责人: RICHARD D CUMMINGS
• 金额: $ 51.43万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-20 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8900161
• 关键词: Adopted; Adult; Anti-Inflammatory Agents; Anti-inflammatory; Antigen-Presenting Cells; Antigens; Avidity; Binding; Binding Proteins; Biological; Biology; C Type Lectin Receptors; Cell physiology; Cells; Chronic; Clinical Trials; Dendritic Cells; Disease; Double-Blind Method; Equilibrium; Experimental Autoimmune Encephalomyelitis; Generations; Glycoproteins; Helminths; Human; Immune response; Immune system; Immunity; Immunotherapy; In Vitro; Infection; Inflammation; Inflammatory; Inflammatory Bowel Diseases; Inflammatory Response; Interdisciplinary Study; Intestines; Life; Ligands; Link; Lipids; Mediating; Microarray Analysis; Modeling; Molecular; Multiple Sclerosis; Mus; Parasites; Pathogenesis; Pattern; Phenotype; Physiologic pulse; Play; Polysaccharides; Property; Proteins; Regulation; Regulatory T-Lymphocyte; Role; Schistosoma mansoni; Shapes; Signal Pathway; Signal Transduction; Stimulus; Structure; Surface; T-Lymphocyte; Testing; Tissues; Toll-like receptors; Trichuris; United States; adaptive immunity; density; egg; in vivo; innovation; macrophage; public health relevance; receptor; receptor-mediated signaling; response; success

DESCRIPTION (provided by applicant): Infections with parasitic worms (helminths) suppress inflammation in a variety of human inflammatory disorders. It is thought that worms or their products induce regulatory T (Treg) cells and alternatively activated macrophages that dampen the effector functions of inflammatory T cells. However, the helminth immunoregulatory mechanisms are still incompletely understood. The regulation of inflammatory responses is mainly mediated via the innate immune system through antigen presenting cells (APC), including dendritic cells (DC) and macrophages (MΦ). DC and MΦ have unique plasticity in adopting various functional phenotypes through specific signaling via surface receptors, such as Toll- like receptors (TLRs) and glycan-binding proteins including C-type lectin receptors (CLRs). Molecular cross-talk of CLR- and TLR-mediated signals in DC is the main determinant that shapes the balance between immunity and tolerance. Our central hypothesis is that specific glycans of helminths and their spatial presentation induce CLR-mediated signaling pathways in APC, which contribute to the generation of anti-inflammatory and regulatory adaptive immune responses that confer protection against inflammation. To test this hypothesis we propose 3 specific aims. (Aim 1a) We will identify the glycan ligands of T. suis and S. mansoni that bind to specific CLRs on DC and MΦ by glycan microarray analysis; (1b) We will define the relationship between the avidity of glycan-binding by CLRs and the capacity of the APC to internalize the glycans via these receptors. (Aim 2a) We will define the signaling pathways induced by glycans of T. suis and S. mansoni glycoproteins, and their influence on TLR-induced signaling pathways; (2b) We will define how the structural composition and spatial presentation of the helminth glycans relate to their capacity to generate anti-inflammatory-type APC. (Aim 3a) We will define how DC pulsed with selected helminth glycans suppress the generation of inflammatory T cells; (3b) We will explore the relationship between the capacity of selected glycans to induce anti-inflammatory properties in APC in vitro, and their capacity to induce host protection in vivo, using the murine model for experimental autoimmune encephalomyelitis (EAE).

描述（由申请人提供）：寄生蠕虫（蠕虫）感染可抑制多种人类炎症性疾病中的炎症。据认为，蠕虫或其产物诱导调节性T（Treg）细胞和替代性激活的巨噬细胞，从而抑制炎症的效应器功能。然而，蠕虫的免疫调节机制仍不完全清楚，炎症反应的调节主要是通过抗原呈递细胞通过先天免疫系统介导的。 (APC)，包括树突细胞 (DC) 和巨噬细胞 (MΦ) DC 和 MΦ 通过表面受体（例如 Toll 样受体 (TLR) 和聚糖结合蛋白（包括 C））采用各种功能表型，具有独特的可塑性。 DC 中 CLR 和 TLR 介导的信号的分子串扰是决定免疫和耐受性之间平衡的主要决定因素。蠕虫的特定聚糖及其空间表达会诱导 APC 中 CLR 介导的信号通路，从而有助于产生抗炎和调节性适应性免疫反应，从而提供针对炎症的保护。为了检验这一假设，我们提出了 3 个具体目标。 ) 我们将通过聚糖微阵列分析鉴定猪 T. suis 和 S. mansoni 与 DC 和 MΦ 上特定 CLR 结合的聚糖配体 (1b) 我们将定义亲合力之间的关系； CLR 的聚糖结合以及 APC 通过这些受体内化聚糖的能力（目标 2a）我们将定义 T. suis 和 S. mansoni 糖蛋白的聚糖诱导的信号传导途径，以及它们对 TLR 诱导的信号传导的影响。 (2b) 我们将定义蠕虫聚糖的结构组成和空间呈现如何与其产生抗炎型 APC 的能力相关（目标 3a）我们将定义 DC 如何产生。 (3b) 我们将使用实验性自身免疫性脑脊髓炎 (EAE) 小鼠模型，探索所选聚糖在体外诱导 APC 抗炎特性的能力与其在体内诱导宿主保护的能力之间的关系。