Extracellular matrix and immune regulation in autoimmune diabetes

自身免疫性糖尿病的细胞外基质和免疫调节

• 批准号: 8875584
• 负责人: Paul L Bollky
• 金额: $ 33.75万
• 依托单位: STANFORD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8875584
• 关键词: Adjuvant; Antigens; Autoimmune Diabetes; Autoimmunity; Binding; CD44 gene; Catabolism; Cell physiology; Cells; Chronic; Data; Environment; Extracellular Matrix; Goals; Healed; Hyaluronan; Immune; Immune Tolerance; Infection; Inflammation; Inflammatory; Insulin-Dependent Diabetes Mellitus; Interleukin-10; Interleukin-2; Islets of Langerhans; Knowledge; Link; Maps; Mediating; Modeling; Molecular Weight; Mus; Pattern; Prevention; Production; Protein Isoforms; Regulation; Regulatory T-Lymphocyte; Role; Sepsis; Signal Transduction; Site; Stat5 protein; T memory cell; T-Lymphocyte; TNFRSF11B gene; Tissues; Vaccination; Vaccines; Variant; base; cell type; crosslink; cytokine; healing; in vivo; injured; innovation; islet; prevent; response; tool; vaccine development

DESCRIPTION (provided by applicant): The inflammatory milieu is a decisive factor in autoimmunity and yet we know very little about how the tissue environment contributes to immune regulation. This knowledge is essential if we are to devise strategies that effectively suppress autoimmunity in inflamed islets and prevent type 1 diabetes (T1D). We have recently determined that high molecular weight hyaluronan (HMW-HA), a component of the extracellular matrix (ECM) of healing tissues, promotes the stability and function of FoxP3+ regulatory T-cells (Treg). HMW-HA does this by crosslinking CD44 and substituting for IL-2 in the IL-2R/STAT5 signaling Treg required for Foxp3 expression and production of IL-10, a key immunoregulatory cytokine. Low molecular weight hyaluronan (LMW-HA), generated from HMW-HA catabolism during infection and chronic inflammation, cannot crosslink CD44 and inhibits Treg function. These data support a model whereby HA integrity governs Treg function in injured and healing tissues. This model predicts that receptivity to HMW-HA signals may govern regulatory T-cell function in inflamed tissues. Indeed, we find that FoxP3+ Treg from T1D subjects have diminished expression of CD44v6, a CD44 variant isoform involved in HMW-HA binding. Reduced CD44v6 expression might impair receptivity to HMW- HA tissue integrity signals and thereby undermine Treg function and persistence in vivo. Our model also predicts that it may be possible to prevent autoimmunity by supporting HA integrity. In healing tissues, HMW-HA degradation is prevented by TSG-6, an HA-binding molecule (hyaladherin) that covalently links HA strands. TSG-6 has been used experimentally to treat sepsis and other forms of inflammation but its value in autoimmune diabetes is unknown. Finally, it may be possible to use HMW-HA to build immune tolerance to auto-antigens. We recently discovered that memory T-cells become IL-10-producing TR1 regulatory T-cells when they encounter their cognate antigen in the context of HMW-HA. Building on this finding, we have developed HMW-HA for use as a tolerizing adjuvant in an intranasal vaccine. Here, we will develop tolerizing vaccination as a tool for autoimmunity prevention. Our applications has three aims that each interrogate different aspects of the relationship between HMW-HA and regulatory T-cell function. They are: 1) to determine whether Treg in TID have impaired responses to HMW-HA, 2) to determine if strategies to promote HMW-HA integrity can prevent autoimmune diabetes, and 3) to develop a vaccine to promote auto-antigen specific immune tolerance using HMW-HA as a tolerizing adjuvant. The unifying goal of these studies is to use HMW-HA mediated tissue integrity signals to prevent autoimmune diabetes.

描述（由申请人提供）：炎症环境是自身免疫的决定性因素，但我们对组织环境如何促进免疫调节知之甚少。如果我们要制定有效抑制发炎胰岛自身免疫并预防 1 型糖尿病 (T1D) 的策略，这些知识至关重要。 我们最近确定，高分子量透明质酸 (HMW-HA) 作为愈合组织细胞外基质 (ECM) 的组成部分，可促进 FoxP3+ 调节性 T 细胞 (Treg) 的稳定性和功能。 HMW-HA 通过交联 CD44 并取代 IL-2R/STAT5 信号 Treg 中的 IL-2 来实现这一点，而 IL-10 是 Foxp3 表达和产生 IL-10（一种关键的免疫调节细胞因子）所需的。低分子量透明质酸 (LMW-HA) 在感染和慢性炎症过程中由 HMW-HA 分解代谢产生，不能交联 CD44 并抑制 Treg 功能。这些数据支持一个模型，即 HA 完整性控制受伤和愈合组织中的 Treg 功能。该模型预测 HMW-HA 信号的感受性可能控制发炎组织中的调节性 T 细胞功能。事实上，我们发现来自 T1D 受试者的 FoxP3+ Treg 的 CD44v6 表达减少，CD44v6 是一种参与 HMW-HA 结合的 CD44 变体亚型。 CD44v6 表达减少可能会损害 HMW-HA 组织完整性信号的接受性，从而破坏 Treg 功能和体内持久性。 我们的模型还预测，通过支持 HA 完整性可能可以预防自身免疫。在愈合组织中，TSG-6 可防止 HMW-HA 降解，TSG-6 是一种共价连接 HA 链的 HA 结合分子（玻璃粘着素）。 TSG-6 已在实验中用于治疗脓毒症和其他形式的炎症，但其在自身免疫性糖尿病中的价值尚不清楚。 最后，也许可以使用 HMW-HA 来建立对自身抗原的免疫耐受。我们最近发现，当记忆 T 细胞在 HMW-HA 环境中遇到同源抗原时，它们会变成产生 IL-10 的 TR1 调节 T 细胞。基于这一发现，我们开发了 HMW-HA，用作鼻内疫苗的耐受佐剂。在这里，我们将开发耐受疫苗 作为预防自身免疫的工具。我们的应用有三个目标，每个目标都探讨 HMW-HA 和调节性 T 细胞功能之间关系的不同方面。它们是：1) 确定 TID 中的 Treg 对 HMW-HA 的反应是否受损，2) 确定促进 HMW-HA 完整性的策略是否可以预防自身免疫性糖尿病，3) 开发一种疫苗，使用 HMW-HA 作为耐受佐剂来促进自身抗原特异性免疫耐受。这些研究的统一目标是利用 HMW-HA 介导的组织完整性信号来预防自身免疫性糖尿病。