PhD Scientific Days 2023

Molecular Sciences IV.

The effect of the JAK inhibitor tofacitinib in experimental autoimmune skin blistering

Text of the abstract

Introduction: Subepidermal autoimmune skin blistering diseases are characterized by autoantibody formation against components of the dermal-epidermal junction, leading to local proliferation and activation of inflammatory cells and consequent dissociation of the dermo-epidermal junction. Our previous experiments with gene-deficient mice have suggested the role of tyrosine kinase signalling pathways in the development of autoimmune skin blistering. Tofacitinib is a small molecule JAK inhibitor registered for the treatment of several autoimmune diseases. The effect of tofacitinib on the development of autoimmune blistering diseases is currently unknown.
Aims: We aimed to investigate the effect of systemic tofacitinib treatment in a widely used animal model of autoantibody-induced skin blistering.
Methods: Wild-type mice were treated twice daily with 16 or 50 mg/kg tofacitinib by oral gavage. Experimental autoimmune skin blistering was induced by subcutaneous injection of antibodies against type VII collagen (C7). The extent of the skin lesions and the appearance of erosions were then monitored for 14 days. Histological changes were assessed using H&E-stained ear and tongue sections. The in vitro effects of tofacitinib on neutrophils were investigated in human skin separation assays and Transwell migration experiments.
Results: Macroscopic examination revealed a significant dose-dependent reduction of skin symptoms of skin blistering disease in tofacitinib-treated mice. A dose of 50 mg/kg tofacitinib reduced symptoms by more than 70% overall, and inhibited the appearance of more severe lesions particularly effectively. Dermo-epidermal separation and blister formation was significantly reduced in tongue sections of tofacitinib-treated mice. Tofacitinib inhibited the migration of neutrophil granulocytes observed under in vitro conditions, but did not affect the development of an inflammatory environment in vivo. Tofacitinib also did not affect human skin separation in vitro in the presence of anti-C7 antibodies.
Conclusion: Systemic tofacitinib therapy inhibits the development of anti-C7-induced skin blistering. This may be due to the inhibition of the migratory ability of neutrophils by tofacitinib. Our results raise the possibility of the therapeutic use of tofacitinib in autoimmune skin blistering diseases.
Funding: TKP2021-EGA-29; SEMTRHEUM project