Mechanism-Based Wound Healing by Activation of gamma delta T Cells

 描述(申请人提供)：上皮屏障组织，包括皮肤，提供了身体和环境之间的接口。皮肤持续暴露在损伤中需要有效的组织修复过程。Gd T细胞优先存在于上皮组织中，在那里它们发挥免疫监视功能，并能对组织损伤做出快速反应。表皮GdT细胞通过产生生长因子、细胞因子和趋化因子来调节伤口修复的炎症和再上皮化阶段，从而促进伤口愈合。共刺激信号是gd T细胞有效激活和参与伤口愈合所必需的，由gd T细胞上的连接黏附分子样蛋白(JAML)和损伤角质形成细胞表达的腺病毒受体(CAR)和其配体Coxsackie结合而传递。在慢性创面患者中，表皮GdT细胞是无能的，不能贡献创面愈合功能。JAML-CAR相互作用在这些患者中被失调，这表明缺乏对gd T细胞的共刺激信号可能是导致愈合受损的原因。我们推测，通过将JAML配体持续输送到创面，向gd T细胞提供共刺激信号将加速慢性创面的愈合。我们将开发可降解的水凝胶，将JAML或CAR结合的配体局部输送到慢性伤口，然后评估这些凝胶对gdT细胞介导的伤口愈合机制的影响，以检验这一假说。老年人、残疾人、糖尿病患者和其他患者有发生慢性伤口的风险，这不仅会影响患者的发病率和死亡率，而且还会增加医疗保健负担。如果共刺激配体的传递促进了愈合，这里开发的策略将成为未来加速人类慢性伤口愈合的方法的基础。

 DESCRIPTION (provided by applicant): Epithelial barrier tissues, including the skin, provide an interface between the body and the environment. The constant exposure to injury in the skin requires efficient tissue repair processes. gd T cells preferentially reside in epithelial tissues where they perform immune surveillance functions and can rapidly respond to tissue injury. Epidermal gd T cells contribute to wound healing through production of growth factors, cytokines and chemokines that regulate the inflammatory and reepithelialization phases of wound repair. Costimulatory signals are required for effective gd T cell activation and participation in wound healing and are delivered by junctional adhesion molecule-like protein (JAML) on gd T cells binding to its ligand Coxsackie and Adenovirus receptor (CAR) expressed by wounded keratinocytes. Epidermal gd T cells are anergic and unable to contribute wound healing functions in patients with chronic wounds. JAML-CAR interactions are dysregulated in these patients suggesting that lack of costimulatory signals for gd T cells may be responsible for the impaired healing. We hypothesize that providing costimulatory signals to gd T cells through sustained delivery of JAML ligands to wounds will accelerate healing of chronic wounds. We will test this hypothesis by developing degradable hydrogels for topical delivery of JAML- or CAR-binding ligands to chronic wounds and then evaluating the effects of these gels on mechanisms of gd T cell-mediated wound healing. The elderly, disabled, diabetic and other patients are at risk for development of chronic wounds that not only affect patient morbidity and mortality but are also an increasing healthcare burden. If delivery of costimulatory ligands improves healing, the strategies developed here will be the basis of future approaches for acceleration of healing of human chronic wounds.