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



 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.