Extracellular matrix and immune regulation in 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中自身免疫和预防1型糖尿病（T1 D）的策略，这些知识是必不可少的。 我们最近已经确定，高分子量透明质酸（HMW-HA），愈合组织的细胞外基质（ECM）的组分，促进FoxP 3+调节性T细胞（Treg）的稳定性和功能。HMW-HA通过交联CD 44并取代Foxp 3表达和产生IL-10（一种关键的免疫调节细胞因子）所需的IL-2 R/STAT 5信号转导Treg中的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催化剂产生，不能交联CD 44并抑制Treg功能。这些数据支持HA完整性在损伤和愈合组织中控制Treg功能的模型。该模型预测，HMW-HA信号的接受性可能会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T1 D受试者的FoxP 3 + Treg具有降低的CD 44 v6（一种参与HMW-HA结合的CD 44变体同种型）表达。降低的CD 44 v6表达可能损害对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完整性来预防自身免疫是可能的。在愈合组织中，HMW-HA降解被TSG-6阻止，TSG-6是一种共价连接HA链的HA结合分子（透明质酸粘蛋白）。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，可能使用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的背景下遇到其同源抗原时，它们成为产生IL-10的TR 1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 作为自身免疫预防的工具。我们的应用程序有三个目标，每个询问HMW-HA和调节T细胞功能之间的关系的不同方面。它们是：1）确定TID中的Treg是否具有受损的对HMW-HA的应答，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，和3）开发使用HMW-HA作为耐受化佐剂促进自身抗原特异性免疫耐受的疫苗。这些研究的统一目标是使用HMW-HA介导的组织完整性信号来预防自身免疫性糖尿病。

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.