The human skin organ culture model as an optimal complementary tool for murine pemphigus models

Abstract

Pemphigus is a severe autoimmune bullous disease of the skin and/or mucous membranes caused by autoantibodies that mainly target the adhesion proteins desmoglein (Dsg) 3 and/or Dsg1. Clinically, pemphigus is characterized by flaccid blistering, leading to severe water and electrolyte loss. Before the introduction of corticosteroid treatment, the disease turned out to be fatal in many cases. Despite recent therapeutic improvements, treatment of pemphigus patients is centred on prolonged systemic immunosuppression and remains challenging. Current drug development for pemphigus has a strong focus on disease-causing B cells and autoantibodies and, more recently, also on modulating autoantibody-induced tissue pathology and keratinocyte signalling. This drug development requires reliable pre-clinical model systems replicating the pathogenesis of the human disease. Among those are neonatal and adult mouse models based on the transfer of Dsg3, Dsg1/3 or Dsg1-specific autoantibodies. To reduce the number of animal experiments, we recently established a standardized human skin organ culture (HSOC) model for pemphigus. This model reproduces the clinical phenotype of autoantibody-induced tissue pathology in pemphigus vulgaris. For induction of blistering, a recombinant single-chain variable fragment (scFv) targeting both Dsg1 and 3 is injected into pieces of human skin (obtained from plastic surgeries). Further characterization of the HSOC model demonstrated that key morphologic, molecular and immunologic features of pemphigus are being replicated. Thus, the pemphigus HSOC model is an excellent alternative to pemphigus animal model systems that are based on the transfer of (auto)antibodies.

Blocking soluble Fas Ligand ameliorates pemphigus: PC111 efficacy in ex-vivo human pemphigus models

“…In order to confirm the efficacy of PC111 in a human context, we used two independent protocols of pemphigus in human skin organ culture (HSOC) models. While the startup PinCell was in the process of refining the proof of concept on the effect of PC111 in human pemphigus, Prof. Detlef Zillikens, member of PinCell Scientific Advisory Board, inspired us by strongly recommending the use of 3D ex-vivo human models given that they are optimal complementary tools for in vivo pemphigus models ( 20 ).…”