title: Adenoviral delivery of IL-1 receptor antagonist abrogates disease activity during the development of autoimmune arthritis in IL-1 receptor antagonist-deficient mice.
abstract: Currently available treatments for rheumatoid arthritis (RA) are limited in terms of their long-term effects and their abilities to control disease progression. Interleukin-1 receptor antagonist (IL-1Ra) is a natural inhibitor of the biologic actions of IL-1, which is known to promote inflammation and degeneration of the joint. In this study, we investigated whether human IL-1Ra gene transfer is effective at treating an established experimental arthritis model. A recombinant adenovirus carrying the gene that encode human hIL-1Ra and GFP (Ad.hIL-1Ra/GFP) was administered by intra-articular injection into the ankle joints of the mice with established the IL-1Ra-deficient Balb/cA mice (IL-1Ra(-/-)), which develop spontaneously chronic inflammatory arthropathy. The effects of two injections of Ad.hIL-1Ra/GFP or control virus with no inserted target gene (Ad.GFP) were compared with the effects of PBS injection with respect to the clinical characteristics of arthritis, as determined by articular index scores, histopathological and immunological assays. We further divided the outcomes of Ad.hIL-1Ra/GFP gene therapy in IL-1Ra(-/-) mice according arthritis stage; early stage and chronic stage corresponding to 8 and 15 weeks of age, respectively. Intra-articular injections of Ad.hIL-1Ra/GFP reduced arthritis severity and footpad swelling compared with control groups treated with Ad.GFP or PBS in early stage IL-1Ra(-/-) mice. Moreover, the histopathology of the ankle joints of IL-1Ra(-/-) mice treated with Ad.hIL-1Ra/GFP showed a significant decrease in synovial proliferation and inflammatory cell infiltration, and preserved proteoglycan levels in the joints of early stage IL-1Ra(-/-) mice compared with the control mice. Moreover, Ad.hIL-1Ra/GFP treated mice showed reduced levels of inflammatory T helper type 1 (Th1) driven IgG2a antibodies to collagen type II but increased levels Th2 driven IgG1 antibody. These results suggest that adenovirus-mediated gene transfer of IL-1Ra may be a promising therapeutic option in the early stage of autoimmune arthritis.
authors.affiliation: Department of Internal Medicine WHO Collaborating Center of Viral Hepatitis, Catholic Research Institutes of Medical Science, The Catholic University of Korea, Seoul, South Korea.
authors.forename: Wonhee
authors.initials: W
authors.lastname: Hur
authors.forename: Mi-La
authors.initials: ML
authors.lastname: Cho
authors.forename: Seung Kew
authors.initials: SK
authors.lastname: Yoon
authors.forename: So Yeon
authors.initials: SY
authors.lastname: Kim
authors.forename: Ji-Hyeon
authors.initials: JH
authors.lastname: Ju
authors.forename: Joo-Yeon
authors.initials: JY
authors.lastname: Jhun
authors.forename: Seong-Bum
authors.initials: SB
authors.lastname: Heo
authors.forename: Young-Mee
authors.initials: YM
authors.lastname: Moon
authors.forename: So-Youn
authors.initials: SY
authors.lastname: Min
authors.forename: Sung-Hwan
authors.initials: SH
authors.lastname: Park
authors.forename: Ho-Youn
authors.initials: HY
authors.lastname: Kim
mesh_terms: D000256:Adenoviridae; D000818:Animals; D001169:Arthritis, Experimental / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D001172:Arthritis, Rheumatoid / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D015316:Genetic Therapy; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000628:therapy; D053590:Interleukin 1 Receptor Antagonist Protein; D007596:Joints / Q000276:immunology / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D012795:Sialoglycoproteins / Q000235:genetics / Q000276:immunology*; D018418:Th2 Cells / Q000276:immunology
chemical_list: C507763:IL1RN protein, human; C507764:Il1rn protein, mouse; D007074:Immunoglobulin G; D053590:Interleukin 1 Receptor Antagonist Protein; D012795:Sialoglycoproteins