title: Type I IFNs Regulate Inflammation, Vasculopathy, and Fibrosis in Chronic Cutaneous Graft-versus-Host Disease.
abstract: Type I IFNs play a critical role in the immune response to viral infection and may also drive autoimmunity through modulation of monocyte maturation and promotion of autoreactive lymphocyte survival. Recent demonstrations of type I IFN gene signatures in autoimmune diseases, including scleroderma, led us to investigate the pathological role of IFNs in a preclinical model of sclerodermatous graft-versus-host disease. Using a neutralizing Ab against the type I IFN receptor IFNAR1, we observed a marked reduction in dermal inflammation, vasculopathy, and fibrosis compared with that seen in the presence of intact IFNAR1 signaling. The ameliorative effects of IFNAR1 blockade were restricted to the skin and were highly associated with inhibition of chronic vascular injury responses and not due to the inhibition of the T or B cell alloresponse. Inhibition of IFNAR1 normalized the overexpression of IFN-inducible genes in graft-versus-host disease skin and markedly reduced dermal IFN-α levels. Depletion of plasmacytoid dendritic cells, a major cellular source of type I IFNs, did not reduce the severity of fibrosis or type I IFN gene signature in the skin. Taken together, these studies demonstrate an important role for type I IFN in skin fibrosis, and they provide a rationale for IFNAR1 inhibition in scleroderma.
authors.affiliation: Respiratory, Inflammation and Autoimmunity Department, MedImmune, LLC, Gaithersburg, MD 20878; delaneyt@medimmune.com.
authors.forename: Tracy A
authors.initials: TA
authors.lastname: Delaney
authors.affiliation: Translational Medicine and Pharmacogenomics Department, MedImmune, LLC, Gaithersburg, MD 20878;
authors.forename: Chris
authors.initials: C
authors.lastname: Morehouse
authors.affiliation: Translational Medicine and Pharmacogenomics Department, MedImmune, LLC, Gaithersburg, MD 20878;
authors.forename: P Zachary
authors.identifier: 0000-0002-7413-6539
authors.initials: PZ
authors.lastname: Brohawn
authors.affiliation: Respiratory, Inflammation and Autoimmunity Department, MedImmune, LLC, Gaithersburg, MD 20878;
authors.forename: Christopher
authors.identifier: 0000-0002-3858-318X
authors.initials: C
authors.lastname: Groves
authors.affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110;
authors.forename: Marco
authors.initials: M
authors.lastname: Colonna
authors.affiliation: Cellular Biomedicine Group, Inc., Palo Alto, CA 94301; and.
authors.forename: Yihong
authors.initials: Y
authors.lastname: Yao
authors.affiliation: Respiratory, Inflammation and Autoimmunity Department, MedImmune, LLC, Gaithersburg, MD 20878;
authors.forename: Miguel
authors.initials: M
authors.lastname: Sanjuan
authors.affiliation: Centers for Therapeutic Innovation, Pfizer, Inc., Boston, MA 02115.
authors.forename: Anthony J
authors.identifier: 0000-0001-8802-985X
authors.initials: AJ
authors.lastname: Coyle
mesh_terms: D000818:Animals; D019138:Antibodies, Blocking / Q000008:administration & dosage; D001323:Autoantibodies / Q000097:blood; D003713:Dendritic Cells / Q000276:immunology*; D004195:Disease Models, Animal; D005260:Female; D005355:Fibrosis; D005786:Gene Expression Regulation; D006086:Graft vs Host Disease / Q000276:immunology*; D006801:Humans; D007249:Inflammation / Q000276:immunology*; D016898:Interferon-alpha / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D053633:Receptor, Interferon alpha-beta / Q000276:immunology; D012595:Scleroderma, Systemic / Q000276:immunology*; D015398:Signal Transduction; D012867:Skin / Q000473:pathology*; D014652:Vascular Diseases / Q000276:immunology*
chemical_list: D019138:Antibodies, Blocking; D001323:Autoantibodies; C508032:Ifnar1 protein, mouse; D016898:Interferon-alpha; D053633:Receptor, Interferon alpha-beta