title: Viral IL-10 and soluble TNF receptor act synergistically to inhibit collagen-induced arthritis following adenovirus-mediated gene transfer.
abstract: Viral IL-10 (vIL-10) and soluble TNF receptor (sTNFR) are anti-inflammatory proteins that can suppress collagen-induced arthritis (CIA). These and related proteins have shown efficacy in the treatment of human rheumatoid arthritis; however, neither alone is able to completely suppress disease. Furthermore, they have short half-lives, necessitating frequent administration. To determine the ability of these proteins to act synergistically following gene transfer, arthritis was induced in DBA/1 male mice by immunization with type II collagen on days 0 and 21. Mice were injected i.v. either before disease onset (day 20) or after disease onset (day 28) with 1010 particles of adenovirus encoding vIL-10, a soluble TNF receptor-IgG1 fusion protein (sTNFR-Ig), a combination of both vectors, or a control vector lacking a transgene. Significant synergism was observed with the combination of vIL-10 and sTNFR-Ig, with a substantial reduction in both the incidence and severity of disease as well as inhibition of progression of established disease. sTNFR-Ig alone had no effect on CIA. vIL-10 alone inhibited disease when given before disease onset, but had minimal effect on established disease. Both proteins inhibited spleen cell proliferation and IFN-gamma secretion in response to stimulation with type II collagen, but only vIL-10 reduced the synovial mRNA levels of the proinflammatory cytokines IL-1beta, TNF-alpha, and IL-6. These findings demonstrate that vIL-10 and sTNFR-Ig act synergistically in suppressing CIA and suggest that gene transfer offers a potential therapeutic modality for the treatment of arthritis.
authors.affiliation: William S. Rowe Division of Rheumatology, Children's Hospital Medical Center, Cincinnati, OH 45229, USA.
authors.forename: K N
authors.initials: KN
authors.lastname: Kim
authors.forename: S
authors.initials: S
authors.lastname: Watanabe
authors.forename: Y
authors.initials: Y
authors.lastname: Ma
authors.forename: S
authors.initials: S
authors.lastname: Thornton
authors.forename: E H
authors.initials: EH
authors.lastname: Giannini
authors.forename: R
authors.initials: R
authors.lastname: Hirsch
mesh_terms: D000256:Adenoviridae / Q000235:genetics* / Q000276:immunology; D000818:Animals; D001169:Arthritis, Experimental / Q000235:genetics* / Q000276:immunology / Q000517:prevention & control*; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism; D003094:Collagen / Q000276:immunology*; D016207:Cytokines / Q000096:biosynthesis / Q000235:genetics; D004357:Drug Synergism; D000068800:Etanercept; D018014:Gene Transfer Techniques; D005822:Genetic Vectors / Q000008:administration & dosage; D006614:Hindlimb; D006801:Humans; D007074:Immunoglobulin G / Q000096:biosynthesis / Q000235:genetics; D016753:Interleukin-10 / Q000008:administration & dosage / Q000235:genetics / Q000502:physiology*; D008213:Lymphocyte Activation / Q000235:genetics; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D012333:RNA, Messenger / Q000096:biosynthesis; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics / Q000502:physiology*; D012995:Solubility; D013601:T-Lymphocytes / Q000276:immunology; D014764:Viral Proteins / Q000008:administration & dosage / Q000235:genetics / Q000502:physiology*
chemical_list: C066460:BCRF1 protein, Human herpesvirus 4; D016207:Cytokines; D007074:Immunoglobulin G; D012333:RNA, Messenger; D018124:Receptors, Tumor Necrosis Factor; D014764:Viral Proteins; D016753:Interleukin-10; D003094:Collagen; D000068800:Etanercept