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Abstract:
Immune-mediated skin diseases (IMSDs) are caused by aberrant activation of immune system which either directly or through stimulation of innate immune cells cause tissue pathology and clinical disease. Although IMSDs are becoming more prevalent and their morbidity rate is high, therapeutic options are still limited accompanied by a high frequency of adverse effects. Here, to identify potential drug candidates for the treatment of IMSDs such as pemphigoid diseases (PDs) and psoriasis, we screened 1200 FDA-approved drugs from Prestwick chemical library (PCL) for their ability to inhibit major pathogenesis-driving adaptive and innate immune cell responses, which includes T-cells, B-cell as well as neutrophil. To achieve cellular activation, T-cells were activated using anti-CD3/CD28, B cells were stimulated with IL-21 and anti-CD40, and neutrophils were activated by immobilized immune complexes. Using defined cut-offs, 39 potential drugs inhibiting T-cell activation, 41 drugs for B-cell activation and 33 drugs for neutrophil activation were identified. Following in depths in vitro validation of identified hits, including toxicity and alternative methods to assess cellular activation, we next explored the impact of in vitro validated drugs in pre-clinical IMSDs model systems, in which disease manifestation depends on activation of either T-cells, B-cells and/or neutrophils. More specifically, we validated the therapeutic efficacy of 5 T-cell inhibitory compounds (mostly heart glycosides and chemotherapeutics) in the T cell–dependent model of Aldara-induced psoriasiform dermatitis. Moreover, in a B cell–dependent immunization-induced model of PD, 3 drugs with so far unknown B cell modulatory activity showed preventive effect. Of those, one drug demonstrated both prophylactic and therapeutic efficacies. Likewise, in a neutrophil-dependent antibody transfer-induced PD mouse model, 3 novel neutrophil inhibitory drugs were validated. Using transcriptome analysis in cooperation with knockout mouse study, we furthermore obtained insights into immune cell functions and pathogenic mechanisms. Collectively, our data provide a vast resource for drug repurposing in (autoimmune) diseases driven by T-cells, B-cells and/or neutrophils. More importantly, the present study provides valuable preclinical evidence for the identified drugs which could ultimately shorten traditional drug development procedure and bring new therapies to the patients faster.
