O15 Improving skin regeneration in JEB by targeting the integrin αvβ6

Abstract Introduction and aims Epithelial integrin αvβ6 has many important roles in skin repair in particular the activation of latent transforming growth factor (TGF)β and its abnormal activity has been associated with chronic wounds. αvβ6 integrin is transiently upregulated in blistered skin; however, it becomes chronic in epidermolysis bullosa skin blistering diseases such as recessive dystrophic epidermolysis bullosa (RDEB) and junctional epidermolysis bullosa (JEB). Here we explore how pathological integrin αvβ6 upregulation in epidermolysis bullosa (EB) is driving defective wound healing, chronic inflammation and fibrosis and if its targeted inhibition improves skin EB symptoms using an inducible JEB disease mouse model. Methods A tamoxifen-inducible JEB disease model with epidermis-specific LAMA3 knockout (KO) was utilized for identifying the αvβ6 integrin signalling changes by immunofluorescent staining and flow cytometry during skin homeostasis and wound healing. To inhibit αvβ6 signalling in JEB skin in vivo a novel αvβ6-blocking antibody 264RAD was injected intraperitoneally for 2 weeks prior skin analysis. Results αvβ6 integrin expression is significantly upregulated in epidermis of JEB KO mice, especially in the blistering areas in comparison with controls. The increased expression of αvβ6 correlates with enhanced inflammatory and fibrosis markers in blistered and wounded skin, suggesting a key role in the pathological mechanisms driving skin disease. The 264RAD treatment showed a strong decrease in integrin αvβ6 expression but also a modest increase in B-cell level accompanied by a rise in mononuclear immune cell populations. Importantly, a reduction in fibrosis around skin blisters and an improvement in wound healing has been observed in JEB KO mice treated with 264RAD. Conclusions The obtained preclinical data reveals abnormal expression of αvβ6 integrin in JEB and indicates that inhibition of αvβ6 is a potential novel therapeutic target to improve skin health and regeneration in JEB and possibly other EB subtypes.