A modified model of graft-versus-host-induced systemic sclerosis (scleroderma) exhibits all major aspects of the human disease.
OBJECTIVE
Diffuse systemic sclerosis (SSc; scleroderma) is a debilitating disease characterized by excessive dermal fibrosis with later progression to internal organs. In addition to the fibrotic component, major aspects of the disease include vascular or circulatory involvement and immune dysregulation evidenced by inflammatory cells in affected tissues and production of autoantibodies. Many animal models resembling this disease have been studied, including genetic models in mice and chickens, challenge with chemicals such as bleomycin or vinyl chloride to induce fibrosis, and models of graft-versus-host (GVH)-induced disease using certain strains of mice with differences in minor histocompatibility loci. The present studies were undertaken to determine if alteration of the induction of GVH-induced scleroderma could result in a model that more fully represented the human condition.


METHODS
Disease was induced by injection of spleen cells from B10.D2 mice into BALB/c mice deficient in mature T and B cells (recombination-activating gene 2 targeted). Dermal thickening, collagen deposition, vasoconstriction, and parameters of immunity were analyzed.


RESULTS
Similar to the human disease, this modified GVH model of SSc demonstrated evidence of dermal thickening, particularly in the extremities, progressive fibrosis of internal organs, vasoconstriction and altered expression of vascularity markers in skin and internal organs, early immune activation, inflammation in skin and internal organs, and autoantibody generation.


CONCLUSIONS
This modified model of GVH-induced SSc exhibits all major components of human disease and is likely to contribute to better understanding of the disease mechanisms and, ultimately, improved treatments for patients.
Ruzek
Melanie C
MC
Genzyme Corporation, Framingham, Massachusetts 01701, USA. melanie.ruzek@genzyme.com
Jha
Sharda
S
Ledbetter
Steve
S
Richards
Susan M
SM
Garman
Richard D
RD
D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology; D003238:Connective Tissue / Q000276:immunology / Q000473:pathology; D004268:DNA-Binding Proteins / Q000235:genetics*; D004195:Disease Models, Animal; D006086:Graft vs Host Disease / Q000276:immunology* / Q000473:pathology; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D018345:Mice, Knockout; D009687:Nuclear Proteins; D012595:Scleroderma, Systemic / Q000276:immunology* / Q000473:pathology; D013601:T-Lymphocytes / Q000166:cytology
D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; C499311:RAG2 protein, human; C499308:Rag2 protein, mouse; C064655:V(D)J recombination activating protein 2