ECM Costimulation of Immunoregulatory Pathways in Airway Inflammation

描述(由申请人提供)：免疫耐受性的丧失是哮喘和过敏的呼吸道炎症的特征。这种免疫失调归因于调节性T细胞数量和功能的减少，包括FoxP3+调节性T细胞(Treg)和产生TR1的IL-10。促进它们的数量和功能的策略将会有很大的治疗益处。Treg和TR1都需要通过IL-2R和TCR来诱导和维持信号。然而，IL-2的可获得性受到严格的调控，而且接触同源抗原通常是间歇性的。因此，在低IL-2和低同源抗原的环境下支持调节性T细胞的机制对免疫动态平衡至关重要。PI已经确定了细胞外基质分子透明质酸(HA)及其受体CD44在促进调节性T细胞的数量和功能方面的作用。CD44在低剂量抗原环境下的交联促进Foxp3+Treg的功能和维持。同样的信号也促进从传统的T细胞前体诱导TR1。基于这一发现，低剂量抗原和HMW-HA鼻腔给药被用来在体内诱导抗原特异性TR1。这些反应是通过IL-2R和TCR信号的协同作用来介导的。由于高分子量透明质酸(HMW-HA)而不是低分子量透明质酸(LMW-HA)能够交联CD44，因此组织完整性在这些作用中起着决定性的作用。 在目标1和2中，PI建议研究HMW-HA在Treg动态平衡中的自然作用。在目标3中，PI将评估鼻腔内接种HMW-HA佐剂诱导的TR1是否可以预防抗原特异性的呼吸道超敏反应小鼠模型的炎症。这是一种新颖的高度创新的免疫调节方法，在预防哮喘和过敏方面具有巨大的潜力。

DESCRIPTION (provided by applicant): The loss of immune tolerance characterizes the airway inflammation seen in asthma and allergy. This immune dysregulation has been attributed to reduced numbers and function of regulatory T-cells, including FoxP3+ regulatory T-cells (Treg) and IL-10 producing TR1. Strategies to promote their numbers and function would have great therapeutic benefit. Both Treg and TR1 require signaling through the IL-2R and the TCR for their induction and maintenance. However, the availability of IL-2 is tightly regulated and exposure to cognate antigens is often intermittent. Mechanisms that support regulatory T-cells in settings of low IL-2 and low cognate antigen are therefore crucial to immune homeostasis. The PI has identified roles for the extracellular matrix molecule hyaluronan (HA) and its receptor CD44 in promoting the number and function of regulatory T-cells. CD44 crosslinking in the setting of low-dose antigen promotes the function and maintenance of Foxp3+ Treg. The same cues also promote the induction of TR1 from conventional T-cell precursors. Building on this finding, intra-nasal delivery of low dose antigen and HMW- HA was used to induce antigen-specific TR1 in vivo. These responses are mediated through synergistic effects on IL-2R and TCR signaling. Because high molecular weight HA (HMW-HA) but not low molecular weight HA (LMW-HA) is capable of crosslinking CD44, tissue integrity plays a decisive role in these effects. In Aims 1 and 2 the PI proposes to investigate the natural role of HMW-HA in Treg homeostasis. In Aim 3 the PI will evaluate whether TR1 induced using intra-nasal vaccination with a HMW-HA adjuvant can prevent inflammation in an antigen-specific mouse model of airway hypersensitivity. This is a novel and highly innovative approach to immune modulation with great potential for the prevention of asthma and allergy.