Cutaneous kinase activity correlates with treatment outcomes following PI3K delta inhibition in mice with experimental pemphigoid diseases

Abstract

Chronic blistering at the skin and/or mucous membranes, accompanied by a varying degree of inflammation, is the clinical hallmark of pemphigoid diseases that impose a major medical burden. Pemphigoid diseases are caused by autoantibodies targeting structural proteins of the epithelial basement membrane. One major pathogenic pathway of skin blistering and inflammation is activation of myeloid cells following Fc gamma receptor-dependent binding to the skin-bound immune complexes. This process requires activation of specific kinases, such as PI3Kδ, which have emerged as potential targets for the treatment of pemphigoid diseases. Yet, it is unknown if global cutaneous kinase activity present in lesional pemphigoid disease correlates with therapeutic effects following treatment with a given target-selective kinase inhibitor. To address this, we here first determined the kinase activity in three different mouse models of pemphigoid diseases: Antibody transfer-induced mucous membrane pemphigoid (MMP), antibody transfer-induced epidermolysis bullosa acquisita (EBA) and immunization-induced EBA. Interestingly, the kinome signatures were different among the three models. More specifically, PI3Kδ was within the kinome activation network of antibody transfer-induced MMP and immunization-induced EBA, but not in antibody transfer-induced EBA. Next, the therapeutic impact of the PI3Kδ-selective inhibitor parsaclisib was evaluated in the three model systems. In line with the kinome signatures, parsaclisib had therapeutic effects in antibody transfer-induced MMP and immunization-induced EBA, but not in autoantibody-induced EBA. In conclusion, kinase activation signatures of inflamed skin, herein exemplified by pemphigoid diseases, correlate with the therapeutic outcomes following kinase inhibition, demonstrated here by the PI3Kδ inhibitor parsaclisib.

Autoimmune bullous dermatoses

“…To identify additional pathophysiologically relevant key molecules and inflammatory pathways suitable for pharmaceutic targeting, ex vivo skin models and mouse models of AIBD are of major relevance. [49][50][51][52]…”

“…For this indication, two innovative phase Ib trials with Dsg3‐specific nanoparticles and Dsg3‐specific CAAR T cells are currently ongoing. To identify additional pathophysiologically relevant key molecules and inflammatory pathways suitable for pharmaceutic targeting, ex vivo skin models and mouse models of AIBD are of major relevance 49–52 …”

Autoimmunity against laminin 332

“…In line with previous findings, methylprednisolone as another first-line therapy for MMP, was also able to reduce the severity of skin, although not oral lesions in this mouse model. In this study, Ghorbanalipoor et al also showed that parsaclisib, a selective inhibitor of phosphoinositide 3-kinase delta (PI3Kd) significantly reduced skin and oral mucosal lesions (99,100). With regard to the characteristic symptom of scarring, typically occurring at the eyes of anti-laminin 332 MMP patients, this mouse model may also be suitable to unravel signaling pathways that contributes to this specific immunopathogenesis.…”

Bullöse Autoimmundermatosen

“…Für diese Indikation laufen gerade zwei innovative Phase‐Ib‐Studien mit Dsg3‐spezifischen Nanopartikeln und Dsg3‐spezifischen CAAR‐T‐Zellen. Um weitere pathophysiologisch relevante Schlüsselmoleküle und Entzündungswege zu identifizieren, die pharmakologisch angesteuert werden können, sind die Ex‐vivo ‐Haut‐ und Mausmodelle der BAID von großer Relevanz 49–52 …”