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: 8719011
• 负责人: Paul L Bollky
• 金额: $ 48.75万
• 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 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8719011
• 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; STAT5A gene; Sepsis; Signal Transduction; Site; 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。如果我们要设计有效抑制炎症胰岛自身免疫和预防1型糖尿病（T1D）的策略，这些知识是必不可少的。我们最近发现，高分子量透明质酸（HMW-HA）是愈合组织细胞外基质（ECM）的一种成分，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并在Foxp3表达和IL-10（一种关键的免疫调节细胞因子）产生所需的IL-2R/STAT5信号Treg中取代IL-2来实现这一点。低分子量透明质酸（LMW-HA）在感染和慢性炎症期间由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HA完整性控制受伤和愈合组织中Treg功能的模型。该模型预测对HMW-HA信号的接受性可能控制炎症组织中的调节性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表达的减少可能会损害对HMW- HA组织完整性信号的接受性，从而破坏Treg在体内的功能和持久性。我们的模型还预测，有可能通过支持HA完整性来预防自身免疫。在愈合组织中，HMW-HA降解被TSG-6阻止，TSG-6是一种HA结合分子（透明质粘附素），共价连接HA链。TSG-6已在实验中用于治疗败血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性。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调节性t细胞。基于这一发现，我们开发了HMW-HA作为鼻内疫苗的耐受性佐剂。在这里，我们将开发耐受性疫苗