A human immune system mouse model for preclinical evaluation of therapies in pemphigoid disease

Pemphigoid diseases (PD) including Epidermolysis bullosa acquisita (EBA) are rare immunoglobulin G (IgG)-driven autoimmune skin blistering diseases with limited therapeutic options. Mechanistically, chronic inflammation in the skin leads to disruption of the dermal-epidermal junction (DEJ) with a crucial contribution of Fc{gamma}R-mediated activation of myeloid immune cells such as neutrophils. Thus, targeting of kinases involved in Fc{gamma}R-dependent activation of myeloid immune cells holds great promise as a therapeutic strategy. In this study, we employ human immune system (HIS) mice featuring all major human leukocytes which allows to investigate the impact of therapeutics on human immune cells in vivo. In a passive transfer approach, repetitive application of collagen VII (COL7c) specific IgG was associated with skin inflammation including infiltration of activated human immune cells and thickening of the epidermis. While application of recombinant human G-CSF boosted myeloid cell maturation and thus disease severity, treatment with Fc{gamma}R-blocking antibodies impaired disease development confirming the crucial role of human cells. Finally, small molecule PDK1 inhibitor BX-795 abrogated development of skin inflammation associated with reduced leukocyte infiltration and activation supporting the role of PDK1 in Fc{gamma}R-driven immune cell activation. This study establishes the first in vivo model of EBA in HIS mice and reveals its suitability for pre-clinical screening and evaluation of therapeutic agents. Importantly, it highlights the potential of kinase inhibition for treatment of EBA.