{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,12]],"date-time":"2026-10-12T13:35:14Z","timestamp":1791812114763,"version":"4.3.4"},"reference-count":48,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2016,7,1]],"date-time":"2016-07-01T00:00:00Z","timestamp":1467331200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/pages\/standard-publication-reuse-rights"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2016,7,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>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-\u03b1 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.<\/jats:p>","DOI":"10.4049\/jimmunol.1502190","type":"journal-article","created":{"date-parts":[[2016,5,26]],"date-time":"2016-05-26T04:08:16Z","timestamp":1464235696000},"page":"42-50","source":"Crossref","is-referenced-by-count":37,"title":["Type I IFNs Regulate Inflammation, Vasculopathy, and Fibrosis in Chronic Cutaneous Graft-versus-Host Disease"],"prefix":"10.1093","volume":"197","author":[{"given":"Tracy A","family":"Delaney","sequence":"first","affiliation":[{"name":"Respiratory, Inflammation and Autoimmunity Department, MedImmune, LLC , Gaithersburg, MD 20878"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chris","family":"Morehouse","sequence":"additional","affiliation":[{"name":"Translational Medicine and Pharmacogenomics Department, MedImmune, LLC , Gaithersburg, MD 20878"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7413-6539","authenticated-orcid":false,"given":"P Zachary","family":"Brohawn","sequence":"additional","affiliation":[{"name":"Translational Medicine and Pharmacogenomics Department, MedImmune, LLC , Gaithersburg, MD 20878"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3858-318X","authenticated-orcid":false,"given":"Christopher","family":"Groves","sequence":"additional","affiliation":[{"name":"Respiratory, Inflammation and Autoimmunity Department, MedImmune, LLC , Gaithersburg, MD 20878"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marco","family":"Colonna","sequence":"additional","affiliation":[{"name":"Department of Pathology and Immunology, Washington University School of Medicine , St. Louis, MO 63110"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yihong","family":"Yao","sequence":"additional","affiliation":[{"name":"Cellular Biomedicine Group, Inc. , Palo Alto, CA 94301"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Miguel","family":"Sanjuan","sequence":"additional","affiliation":[{"name":"Respiratory, Inflammation and Autoimmunity Department, MedImmune, LLC , Gaithersburg, MD 20878"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8802-985X","authenticated-orcid":false,"given":"Anthony J","family":"Coyle","sequence":"additional","affiliation":[{"name":"Centers for Therapeutic Innovation, Pfizer, Inc. , Boston, MA 02115"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2016,7,1]]},"reference":[{"key":"2025030617451683900_r1","doi-asserted-by":"crossref","first-page":"d608","DOI":"10.2741\/trojan","article-title":"Molecular aspects of scleroderma","volume":"7","author":"Trojanowska","year":"2002","journal-title":"Front. Biosci."},{"key":"2025030617451683900_r2","doi-asserted-by":"crossref","first-page":"2437","DOI":"10.1002\/1529-0131(200011)43:11<2437::AID-ANR10>3.0.CO;2-U","article-title":"Severe organ involvement in systemic sclerosis with diffuse scleroderma","volume":"43","author":"Steen","year":"2000","journal-title":"Arthritis Rheum."},{"key":"2025030617451683900_r3","doi-asserted-by":"crossref","first-page":"453","DOI":"10.1038\/nrrheum.2010.102","article-title":"Cellular and molecular aspects of vascular dysfunction in systemic sclerosis","volume":"6","author":"Trojanowska","year":"2010","journal-title":"Nat. Rev. Rheumatol."},{"key":"2025030617451683900_r4","doi-asserted-by":"crossref","first-page":"196","DOI":"10.1007\/s10067-003-0698-1","article-title":"Vascular damage and lack of angiogenesis in systemic sclerosis skin","volume":"22","author":"Konttinen","year":"2003","journal-title":"Clin. Rheumatol."},{"key":"2025030617451683900_r5","doi-asserted-by":"crossref","first-page":"203","DOI":"10.1016\/S0002-9440(10)63289-0","article-title":"Targeted disruption of TGF-\u03b2\/Smad3 signaling modulates skin fibrosis in a mouse model of scleroderma","volume":"165","author":"Lakos","year":"2004","journal-title":"Am. J. Pathol."},{"key":"2025030617451683900_r6","doi-asserted-by":"crossref","first-page":"6","DOI":"10.1006\/clim.1999.4720","article-title":"Anti-sclerotic effect of transforming growth factor-\u03b2 antibody in a mouse model of bleomycin-induced scleroderma","volume":"92","author":"Yamamoto","year":"1999","journal-title":"Clin. Immunol."},{"key":"2025030617451683900_r7","doi-asserted-by":"crossref","first-page":"136","DOI":"10.1007\/s11926-002-0009-x","article-title":"Connective tissue growth factor: a new and important player in the pathogenesis of fibrosis","volume":"4","author":"Leask","year":"2002","journal-title":"Curr. Rheumatol. Rep."},{"key":"2025030617451683900_r8","doi-asserted-by":"crossref","first-page":"156","DOI":"10.1007\/s11926-005-0069-9","article-title":"Scleroderma, fibroblasts, signaling, and excessive extracellular matrix","volume":"7","author":"Ihn","year":"2005","journal-title":"Curr. Rheumatol. Rep."},{"key":"2025030617451683900_r9","doi-asserted-by":"crossref","first-page":"720","DOI":"10.1097\/BOR.0b013e32830e48e8","article-title":"Antitransforming growth factor-\u03b2 therapy in fibrosis: recent progress and implications for systemic sclerosis","volume":"20","author":"Varga","year":"2008","journal-title":"Curr. Opin. Rheumatol."},{"key":"2025030617451683900_r10","doi-asserted-by":"crossref","first-page":"2795","DOI":"10.1172\/JCI77958","article-title":"Fresolimumab treatment decreases biomarkers and improves clinical symptoms in systemic sclerosis patients","volume":"125","author":"Rice","year":"2015","journal-title":"J. Clin. Invest."},{"key":"2025030617451683900_r11","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1146\/annurev.immunol.23.021704.115843","article-title":"Type I interferons (\u03b1\/\u03b2) in immunity and autoimmunity","volume":"23","author":"Theofilopoulos","year":"2005","journal-title":"Annu. Rev. Immunol."},{"key":"2025030617451683900_r12","doi-asserted-by":"crossref","first-page":"135","DOI":"10.1084\/jem.20050500","article-title":"Plasmacytoid predendritic cells initiate psoriasis through interferon-\u03b1 production","volume":"202","author":"Nestle","year":"2005","journal-title":"J. Exp. Med."},{"key":"2025030617451683900_r13","doi-asserted-by":"crossref","first-page":"13544","DOI":"10.1073\/pnas.0506577102","article-title":"Discovering statistically significant pathways in expression profiling studies","volume":"102","author":"Tian","year":"2005","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"2025030617451683900_r14","doi-asserted-by":"crossref","first-page":"664","DOI":"10.1191\/096120300674499064","article-title":"Activation of type I interferon system in systemic lupus erythematosus correlates with disease activity but not with antiretroviral antibodies","volume":"9","author":"Bengtsson","year":"2000","journal-title":"Lupus"},{"key":"2025030617451683900_r15","doi-asserted-by":"crossref","first-page":"1185","DOI":"10.1002\/art.20998","article-title":"Activation of the type I interferon system in primary Sj\u00f6gren\u2019s syndrome: a possible etiopathogenic mechanism","volume":"52","author":"B\u00e5ve","year":"2005","journal-title":"Arthritis Rheum."},{"key":"2025030617451683900_r16","doi-asserted-by":"crossref","first-page":"S4","DOI":"10.1186\/ar2885","article-title":"Type 1 interferons and myositis","volume":"12","author":"Greenberg","year":"2010","journal-title":"Arthritis Res. Ther."},{"key":"2025030617451683900_r17","doi-asserted-by":"crossref","first-page":"694","DOI":"10.1093\/rheumatology\/kei244","article-title":"Signatures of differentially regulated interferon gene expression and vasculotrophism in the peripheral blood cells of systemic sclerosis patients","volume":"45","author":"Tan","year":"2006","journal-title":"Rheumatology (Oxford)"},{"key":"2025030617451683900_r18","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1007\/s00403-007-0737-x","article-title":"Increased expression of 2\u20325\u2032oligoadenylate synthetase and double-stranded RNA dependent protein kinase messenger RNAs on affected skin of systemic sclerosis patients","volume":"299","author":"Coelho","year":"2007","journal-title":"Arch. Dermatol. Res."},{"key":"2025030617451683900_r19","doi-asserted-by":"crossref","first-page":"1010","DOI":"10.1002\/art.22382","article-title":"A macrophage marker, Siglec-1, is increased on circulating monocytes in patients with systemic sclerosis and induced by type I interferons and Toll-like receptor agonists","volume":"56","author":"York","year":"2007","journal-title":"Arthritis Rheum."},{"key":"2025030617451683900_r20","doi-asserted-by":"crossref","first-page":"555","DOI":"10.1089\/jir.2010.0078","article-title":"Interferon-\u03bb: a new addition to an old family","volume":"30","author":"Donnelly","year":"2010","journal-title":"J. Interferon Cytokine Res."},{"key":"2025030617451683900_r21","doi-asserted-by":"crossref","first-page":"369","DOI":"10.1016\/0167-5699(96)10027-X","article-title":"The neglected role of type I interferon in the T-cell response: implications for its clinical use","volume":"17","author":"Belardelli","year":"1996","journal-title":"Immunol. Today"},{"key":"2025030617451683900_r22","doi-asserted-by":"crossref","first-page":"9","DOI":"10.1111\/j.0105-2896.2005.00252.x","article-title":"Interferons as pathogenic effectors in autoimmunity","volume":"204","author":"Baccala","year":"2005","journal-title":"Immunol. Rev."},{"key":"2025030617451683900_r23","doi-asserted-by":"crossref","first-page":"539","DOI":"10.1016\/S1074-7613(04)00108-6","article-title":"Autoimmunity through cytokine-induced dendritic cell activation","volume":"20","author":"Banchereau","year":"2004","journal-title":"Immunity"},{"key":"2025030617451683900_r24","doi-asserted-by":"crossref","first-page":"379","DOI":"10.1016\/S1359-6101(02)00023-0","article-title":"Type I interferons and autoimmunity: lessons from the clinic and from IRF-2-deficient mice","volume":"13","author":"Taki","year":"2002","journal-title":"Cytokine Growth Factor Rev."},{"key":"2025030617451683900_r25","doi-asserted-by":"crossref","first-page":"2366","DOI":"10.4049\/jimmunol.171.5.2366","article-title":"Dendritic cells mediate NK cell help for Th1 and CTL responses: two-signal requirement for the induction of NK cell helper function","volume":"171","author":"Mailliard","year":"2003","journal-title":"J. Immunol."},{"key":"2025030617451683900_r26","doi-asserted-by":"crossref","first-page":"3618","DOI":"10.1002\/art.21383","article-title":"The antiangiogenic tissue kallikrein pattern of endothelial cells in systemic sclerosis","volume":"52","author":"Giusti","year":"2005","journal-title":"Arthritis Rheum."},{"key":"2025030617451683900_r27","doi-asserted-by":"crossref","first-page":"e47952","DOI":"10.1371\/journal.pone.0047952","article-title":"Recombination activating gene-2 regulates CpG-mediated interferon-\u03b1 production in mouse bone marrow-derived plasmacytoid dendritic cells","volume":"7","author":"Luo","year":"2012","journal-title":"PLoS One"},{"key":"2025030617451683900_r28","doi-asserted-by":"crossref","first-page":"711","DOI":"10.1084\/jem.20021553","article-title":"Interferon and granulopoiesis signatures in systemic lupus erythematosus blood","volume":"197","author":"Bennett","year":"2003","journal-title":"J. Exp. Med."},{"key":"2025030617451683900_r29","doi-asserted-by":"crossref","first-page":"1905","DOI":"10.1136\/ard.2010.144485","article-title":"Safety profile and clinical activity of sifalimumab, a fully human anti-interferon \u03b1 monoclonal antibody, in systemic lupus erythematosus: a phase I, multicentre, double-blind randomised study","volume":"70","author":"Merrill","year":"2011","journal-title":"Ann. Rheum. Dis."},{"key":"2025030617451683900_r30","doi-asserted-by":"crossref","first-page":"2029","DOI":"10.1136\/ard.2011.150326","article-title":"Patients with systemic lupus erythematosus, myositis, rheumatoid arthritis and scleroderma share activation of a common type I interferon pathway","volume":"70","author":"Higgs","year":"2011","journal-title":"Ann. Rheum. Dis."},{"key":"2025030617451683900_r31","doi-asserted-by":"crossref","first-page":"1319","DOI":"10.1002\/art.20160","article-title":"A modified model of graft-versus-host-induced systemic sclerosis (scleroderma) exhibits all major aspects of the human disease","volume":"50","author":"Ruzek","year":"2004","journal-title":"Arthritis Rheum."},{"key":"2025030617451683900_r32","doi-asserted-by":"crossref","first-page":"521","DOI":"10.1084\/jem.189.3.521","article-title":"Type I interferons keep activated T cells alive","volume":"189","author":"Marrack","year":"1999","journal-title":"J. Exp. Med."},{"key":"2025030617451683900_r33","doi-asserted-by":"crossref","first-page":"629","DOI":"10.1038\/37648","article-title":"Antiproliferative action of interferon-\u03b1 requires components of T-cell-receptor signalling","volume":"390","author":"Petricoin","year":"1997","journal-title":"Nature"},{"key":"2025030617451683900_r34","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1080\/019021499270268","article-title":"Selective inhibition of collagen gene expression in fibroblasts by an interferon-\u03b3 transgene","volume":"25","author":"Jaffe","year":"1999","journal-title":"Exp. Lung Res."},{"key":"2025030617451683900_r35","first-page":"307","article-title":"Collagen synthesis by human liver (myo)fibroblasts in culture: evidence for a regulatory role of IL-1\u03b2, IL-4, TGF\u03b2 and IFN\u03b3","volume":"23","author":"Tiggelman","year":"1995","journal-title":"J. Hepatol."},{"key":"2025030617451683900_r36","doi-asserted-by":"crossref","first-page":"251","DOI":"10.1016\/S1357-2725(96)00112-4","article-title":"Interferon-\u03b3 regulates collagen and fibronectin gene expression by transcriptional and post-transcriptional mechanisms","volume":"29","author":"Diaz","year":"1997","journal-title":"Int. J. Biochem. Cell Biol."},{"key":"2025030617451683900_r37","doi-asserted-by":"crossref","first-page":"1051","DOI":"10.1517\/14712598.6.10.1051","article-title":"Interferon-\u03b31b for the treatment of idiopathic pulmonary fibrosis","volume":"6","author":"Bouros","year":"2006","journal-title":"Expert Opin. Biol. Ther."},{"key":"2025030617451683900_r38","doi-asserted-by":"crossref","first-page":"S1","DOI":"10.1111\/j.1529-8019.2009.01263.x","article-title":"Cutaneous lesions as initial signs of interferon \u03b1-induced sarcoidosis: report of three new cases and review of the literature","volume":"22","author":"Fantini","year":"2009","journal-title":"Dermatol. Ther. (Heidelb.)"},{"key":"2025030617451683900_r39","doi-asserted-by":"crossref","first-page":"322","DOI":"10.1111\/j.1365-2893.2005.00689.x","article-title":"Interferon \u03b3-1b for the treatment of fibrosis in chronic hepatitis C infection","volume":"13","author":"Muir","year":"2006","journal-title":"J. Viral Hepat."},{"key":"2025030617451683900_r40","first-page":"127","article-title":"Influence of LPS, TNF, TGF-\u03b21 and IL-4 on the expression of MMPs, TIMPs and selected cytokines in rat synovial membranes incubated in vitro","volume":"27","author":"Hyc","year":"2011","journal-title":"Int. J. Mol. Med."},{"key":"2025030617451683900_r41","doi-asserted-by":"crossref","first-page":"iv44","DOI":"10.1136\/ard.2005.042465","article-title":"What are the roles of metalloproteinases in cartilage and bone damage?","volume":"64","author":"Murphy","year":"2005","journal-title":"Ann. Rheum. Dis."},{"key":"2025030617451683900_r42","doi-asserted-by":"crossref","first-page":"L751","DOI":"10.1152\/ajplung.90578.2008","article-title":"MMP9 modulates tight junction integrity and cell viability in human airway epithelia","volume":"296","author":"Vermeer","year":"2009","journal-title":"Am. J. Physiol. Lung Cell. Mol. Physiol."},{"key":"2025030617451683900_r43","doi-asserted-by":"crossref","first-page":"65","DOI":"10.1007\/s00441-011-1186-6","article-title":"Klf10 and Klf11 as mediators of TGF-\u03b2 superfamily signaling","volume":"347","author":"Spittau","year":"2012","journal-title":"Cell Tissue Res."},{"key":"2025030617451683900_r44","doi-asserted-by":"crossref","first-page":"530","DOI":"10.1136\/ard.2010.135772","article-title":"Involvement of functional autoantibodies against vascular receptors in systemic sclerosis","volume":"70","author":"Riemekasten","year":"2011","journal-title":"Ann. Rheum. Dis."},{"key":"2025030617451683900_r45","doi-asserted-by":"crossref","first-page":"e1452","DOI":"10.1371\/journal.pone.0001452","article-title":"Capillary regeneration in scleroderma: stem cell therapy reverses phenotype?","volume":"3","author":"Fleming","year":"2008","journal-title":"PLoS One"},{"key":"2025030617451683900_r46","first-page":"209","article-title":"Induction of apoptosis in human dermal microvascular endothelial cells and infantile hemangiomas by interferon-\u03b1","volume":"117","author":"Sgonc","year":"1998","journal-title":"Int. Arch. Allergy Immunol."},{"key":"2025030617451683900_r47","doi-asserted-by":"crossref","first-page":"5740","DOI":"10.4049\/jimmunol.174.9.5740","article-title":"Novel fibrogenic pathways are activated in response to endothelial apoptosis: implications in the pathophysiology of systemic sclerosis","volume":"174","author":"Laplante","year":"2005","journal-title":"J. Immunol."},{"key":"2025030617451683900_r48","doi-asserted-by":"crossref","first-page":"4893","DOI":"10.4049\/jimmunol.158.10.4893","article-title":"Active oxidants mediate IFN-\u03b1-induced microvascular alterations in rat mesentery","volume":"158","author":"Higuchi","year":"1997","journal-title":"J. Immunol."}],"container-title":["The Journal of Immunology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/197\/1\/42\/62245891\/1502190.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/jimmunol\/article-pdf\/197\/1\/42\/62245891\/1502190.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,3,6]],"date-time":"2025-03-06T18:50:06Z","timestamp":1741287006000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/jimmunol\/article\/197\/1\/42\/7974483"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,7,1]]},"references-count":48,"journal-issue":{"issue":"1","published-print":{"date-parts":[[2016,7,1]]}},"URL":"https:\/\/doi.org\/10.4049\/jimmunol.1502190","relation":{},"ISSN":["0022-1767","1550-6606"],"issn-type":[{"value":"0022-1767","type":"print"},{"value":"1550-6606","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2016,7]]},"published":{"date-parts":[[2016,7,1]]}}}