Extracellular matrix and immune regulation in autoimmune diabetes

描述(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参与免疫调节知之甚少。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。我们最近确定，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，可以促进FoxP3调节T细胞(Treg)的稳定性和功能。HMW-HA通过交联CD44并取代IL-2R/STAT5信号通路中的IL-2来实现这一点，TREG是Foxp3表达和产生IL-10所必需的，IL-10是一种关键的免疫调节细胞因子。低分子量透明质酸(LMW-HA)是在感染和慢性炎症过程中HMW-HA分解代谢产生的，不能与CD44交联会抑制Treg功能。这些数据支持HA完整性管理损伤和愈合组织中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调节性T细胞的功能。事实上，我们发现T1D患者的FoxP3 Treg降低了CD44v6的表达，CD44v6是一种参与HMW-HA结合的CD44变体亚型。CD44v6表达的降低可能会削弱对HMW-HA组织完整性信号的接受性，从而破坏Treg的功能和体内的持久性。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的降解被TSG-6阻止，TSG-6是一种HA结合分子(透明粘附素)，共价连接HA链。TSG-6已被实验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，使用HMW-HA建立对自身抗原的免疫耐受是可能的。我们最近发现，当记忆T细胞在HMW-HA背景下遇到其同源抗原时，它们会成为产生IL-10的TR1调节T细胞。在这一发现的基础上，我们开发了HMW-HA作为鼻腔疫苗的耐受性佐剂。在这里，我们将发展耐受性疫苗接种 作为预防自身免疫的工具。我们的应用有三个目标，每个目标都询问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是否损害了对HMW-HA的反应；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，以HMW-HA作为耐受性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.