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Induction of Scleroderma Fibrosis in Skin‐Humanized Mice by Administration of Anti−Platelet‐Derived Growth Factor Receptor Agonistic Autoantibodies
Author(s) -
Luchetti Michele M.,
Moroncini Gianluca,
Jose Escamez Maria,
Svegliati Baroni Silvia,
Spadoni Tatiana,
Grieco Antonella,
Paolini Chiara,
Funaro Ada,
Avvedimento Enrico V.,
Larcher Fernando,
Del Rio Marcela,
Gabrielli Armando
Publication year - 2016
Publication title -
arthritis and rheumatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.106
H-Index - 314
eISSN - 2326-5205
pISSN - 2326-5191
DOI - 10.1002/art.39728
Subject(s) - medicine , ex vivo , in vivo , fibrosis , monoclonal antibody , scleroderma (fungus) , autoantibody , human skin , pathology , platelet derived growth factor receptor , antibody , immunology , cancer research , growth factor , receptor , biology , genetics , microbiology and biotechnology , inoculation
Objective To describe a skin–SCID mouse chimeric model of systemic sclerosis (SSc; scleroderma) fibrosis based on engraftment of ex vivo–bioengineered skin using skin cells derived either from scleroderma patients or from healthy donors. Methods Three‐dimensional bioengineered skin containing human keratinocytes and fibroblasts isolated from skin biopsy specimens from healthy donors or SSc patients was generated ex vivo and then grafted onto the backs of SCID mice. The features of the skin grafts were analyzed by immunohistochemistry, and the functional profile of the graft fibroblasts was defined before and after treatment with IgG from healthy controls or SSc patients. Two procedures were used to investigate the involvement of platelet‐derived growth factor receptor (PDGFR): 1) nilotinib, a tyrosine kinase inhibitor, was administered to mice before injection of IgG from SSc patient sera (SSc IgG) into the grafts, and 2) human anti‐PDGFR monoclonal antibodies were injected into the grafts. Results Depending on the type of bioengineered skin grafted, the regenerated human skin exhibited either the typical scleroderma phenotype or the healthy human skin architecture. Treatment of animals carrying healthy donor skin grafts with SSc IgG resulted in the appearance of a bona fide scleroderma phenotype, as confirmed by increased collagen deposition and fibroblast activation markers. Results of the experiments involving administration of nilotinib or monoclonal antibodies confirmed the involvement of PDGFR. Conclusion Our results provide the first in vivo demonstration of the fibrotic properties of anti‐PDGFR agonistic antibodies. This bioengineered skin–humanized mouse model can be used to test in vivo the progression of the disease and to monitor response to antifibrotic drugs.