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Inhibition of phosphodiesterase-4 significantly decreases oral mucosa lesions in experimental anti-laminin 332 mucous membrane pemphigoid

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49th Annual ESDR Meeting

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Abstract

Mucous membrane pemphigoid (MMP) is characterized by autoantibodies against the dermal-epidermal-junction and a mucosal disease predominating over skin involvement. As the treatment of MMP patients still relies on high-dose corticosteroids, there is an unmet need for new and more specific therapies. Here, we made use of a recently established experimental model that recapitulated major clinical and immunopathological characteristics of human MMP by the injection of IgG against the murine alpha3 chain of laminin 332 (Lam332) into adult mice. In a prophylactic approach, the specific PDE4 inhibitor roflumilast (ROF) led in 2 independent, blinded experiments, to the reduction of oral lesions compared to vehicle-treated mice as quantified by endoscopy (p=0.029). In contrast, an increase in skin lesions was observed in ROF-treated mice (p<0.0001). In a quasi-therapeutic approach, i.e. when ROF/vehicle was not used until mice had developed first skin lesions, ROF-treated mice showed significantly less oral lesions compared to vehicle-treated mice, while skin lesions did not differ. To investigate the discrepant effect of ROF on oral and skin lesions, a transcriptome analysis of both tissues in ROF- and vehicle-treated anti-Lam332 MMP mice as well as mice injected with normal rabbit IgG was performed. An up-regulation of IL-6 and an impact of CXCL2 were found by Gene Set Enrichment and STRING analysis, respectively, in both the skin and buccal mucosa of vehicle-treated mice. The subsequent incubation of murine keratinocytes with anti-mLam332 IgG resulted in a dose-dependent release of IL-6 and CXCL2, which was inhibited by the addition of ROF. Our data propose IL-6 and CXCL2 as relevant pathogenic factors in MMP and suggest PDE4 inhibition as potential novel treatment options for MMP patients with severe oral lesions.

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© Copyright 2019 Morressier GmbH.
All rights reserved.