Development of a Skin-Humanized Model as a Novel Tool to Investigate the Pathogenesis of Scleroderma

Systemic sclerosis or scleroderma (SSc) is a relatively rare disease characterized by fibrosis of the skin, blood vessels, skeletal muscles and visceral organs that also trait with production of auto-antibodies. The disease produces a devastating impact on the individual, disability and sometimes death as a result of endstage organ failure. Exciting new results have evidence that circulating auto-antibodies against the PDGF receptor (PDGFR), only present in SSc sera, are causally associated with the pro-fibrotic phenotype of SSc fibroblasts. In spite of this significant advance, there are neither effective therapies nor reliable diagnostic/prognostic tools to manage the progression of tissue fibrosis, the main cause of morbidity and mortality in SSc. Even although the study of SSc pathogenesis has greatly benefited from the study of the existing animal models, none of them faithfully replicates the biological complexity of the human disease. A feature remarkably different from what is found in the human SSc lesions is an excessive ECM deposition in the skin as a consequence of an important inflammatory response. With the aim to avoid this problem the development of a system in which fibrosis will be dissociated from active inflammation is mandatory. In this context, we have developed a new model based on the use of skin-humanized mice in which scleroderma is induced by intradermal injection of stimulatory PDGFR autoantibodies isolated from the immunoglobulin repertoire of scleroderma patients. The proposed model recapitulates the fibrotic lesions present in the skin of SSc patients. This system has also allowed to asses the therapeutic capacity of nilotinib, a PDGFR inhibitor already approved for clinical use in haematological disorders. Further studies currently ongoing with the purpose of characterizing key downstream events and pathogenic properties of the anti-PDGFR auto-antibodies using primary fibroblasts isolated from the SSc-humanized skin will advance significantly our limited understanding of SSc etiopathogenesis and in consequence could be clinically significant in scope.