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Proc Natl Acad Sci U S A. Jan 9, 1996; 93(1): 402–406.
PMCID: PMC40246

Suppression of experimental arthritis by gene transfer of interleukin 1 receptor antagonist cDNA.

Abstract

Restoration of the impaired balance between pro- and antiinflammatory cytokines should provide effective treatment of rheumatoid arthritis. Gene therapy has been proposed as an approach for delivery of therapeutic proteins to arthritic joints. Here, we examined the efficacy of antiinflammatory gene therapy in bacterial cell wall-induced arthritis in rats. Human secreted interleukin 1 receptor antagonist (sIL-1ra) was expressed in joints of rats with recurrent bacterial cell wall-induced arthritis by using ex vivo gene transfer. To achieve this, primary synoviocytes were transduced in culture with a retroviral vector carrying the sIL-1ra cDNA. Transduced cells were engrafted in ankle joints of animals prior to reactivation of arthritis. Animals in control groups were engrafted with synoviocytes transduced with lacZ and neo marker genes. Cells continued to express transferred genes for at least 9 days after engraftment. We found that gene transfer of sIL-1ra significantly suppressed the severity of recurrence of arthritis, as assessed by measuring joint swelling and by the gross-observation score, and attenuated but did not abolish erosion of cartilage and bone. The effect of intraarticularly expressed sIL-1ra was essentially local, as there was no significant difference in severity of recurrence between unengrafted contralateral joints in control and experimental groups. We estimate that locally expressed sIL-1ra was about four orders of magnitude more therapeutically efficient than systemically administered recombinant sIL-1ra protein. These findings provide experimental evidence for the feasibility of antiinflammatory gene therapy for arthritis.

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  • Bandara G, Robbins PD, Georgescu HI, Mueller GM, Glorioso JC, Evans CH. Gene transfer to synoviocytes: prospects for gene treatment of arthritis. DNA Cell Biol. 1992 Apr;11(3):227–231. [PubMed]
  • Evans C, Robbins PD. Prospects for treating arthritis by gene therapy. J Rheumatol. 1994 May;21(5):779–782. [PubMed]
  • Roessler BJ, Allen ED, Wilson JM, Hartman JW, Davidson BL. Adenoviral-mediated gene transfer to rabbit synovium in vivo. J Clin Invest. 1993 Aug;92(2):1085–1092. [PMC free article] [PubMed]
  • Makarov SS, Olsen JC, Johnston WN, Schwab JH, Anderle SK, Brown RR, Haskill JS. Retrovirus mediated in vivo gene transfer to synovium in bacterial cell wall-induced arthritis in rats. Gene Ther. 1995 Aug;2(6):424–428. [PubMed]
  • Bandara G, Mueller GM, Galea-Lauri J, Tindal MH, Georgescu HI, Suchanek MK, Hung GL, Glorioso JC, Robbins PD, Evans CH. Intraarticular expression of biologically active interleukin 1-receptor-antagonist protein by ex vivo gene transfer. Proc Natl Acad Sci U S A. 1993 Nov 15;90(22):10764–10768. [PMC free article] [PubMed]
  • Hung GL, Galea-Lauri J, Mueller GM, Georgescu HI, Larkin LA, Suchanek MK, Tindal MH, Robbins PD, Evans CH. Suppression of intra-articular responses to interleukin-1 by transfer of the interleukin-1 receptor antagonist gene to synovium. Gene Ther. 1994 Jan;1(1):64–69. [PubMed]
  • Roessler BJ, Hartman JW, Vallance DK, Latta JM, Janich SL, Davidson BL. Inhibition of interleukin-1-induced effects in synoviocytes transduced with the human IL-1 receptor antagonist cDNA using an adenoviral vector. Hum Gene Ther. 1995 Mar;6(3):307–316. [PubMed]
  • Arend WP, Dayer JM. Inhibition of the production and effects of interleukin-1 and tumor necrosis factor alpha in rheumatoid arthritis. Arthritis Rheum. 1995 Feb;38(2):151–160. [PubMed]
  • Hannum CH, Wilcox CJ, Arend WP, Joslin FG, Dripps DJ, Heimdal PL, Armes LG, Sommer A, Eisenberg SP, Thompson RC. Interleukin-1 receptor antagonist activity of a human interleukin-1 inhibitor. Nature. 1990 Jan 25;343(6256):336–340. [PubMed]
  • Eisenberg SP, Evans RJ, Arend WP, Verderber E, Brewer MT, Hannum CH, Thompson RC. Primary structure and functional expression from complementary DNA of a human interleukin-1 receptor antagonist. Nature. 1990 Jan 25;343(6256):341–346. [PubMed]
  • Dinarello CA, Thompson RC. Blocking IL-1: interleukin 1 receptor antagonist in vivo and in vitro. Immunol Today. 1991 Nov;12(11):404–410. [PubMed]
  • Arend WP. Interleukin-1 receptor antagonist. Adv Immunol. 1993;54:167–227. [PubMed]
  • Miller LC, Lynch EA, Isa S, Logan JW, Dinarello CA, Steere AC. Balance of synovial fluid IL-1 beta and IL-1 receptor antagonist and recovery from Lyme arthritis. Lancet. 1993 Jan 16;341(8838):146–148. [PubMed]
  • Schwab JH, Anderle SK, Brown RR, Dalldorf FG, Thompson RC. Pro- and anti-inflammatory roles of interleukin-1 in recurrence of bacterial cell wall-induced arthritis in rats. Infect Immun. 1991 Dec;59(12):4436–4442. [PMC free article] [PubMed]
  • Dinarello CA. Interleukin-1. Adv Pharmacol. 1994;25:21–51. [PubMed]
  • Sporn SA, Eierman DF, Johnson CE, Morris J, Martin G, Ladner M, Haskill S. Monocyte adherence results in selective induction of novel genes sharing homology with mediators of inflammation and tissue repair. J Immunol. 1990 Jun 1;144(11):4434–4441. [PubMed]
  • Haskill S, Martin G, Van Le L, Morris J, Peace A, Bigler CF, Jaffe GJ, Hammerberg C, Sporn SA, Fong S, et al. cDNA cloning of an intracellular form of the human interleukin 1 receptor antagonist associated with epithelium. Proc Natl Acad Sci U S A. 1991 May 1;88(9):3681–3685. [PMC free article] [PubMed]
  • Miller AD, Rosman GJ. Improved retroviral vectors for gene transfer and expression. Biotechniques. 1989 Oct;7(9):980–990. [PMC free article] [PubMed]
  • Adam MA, Ramesh N, Miller AD, Osborne WR. Internal initiation of translation in retroviral vectors carrying picornavirus 5' nontranslated regions. J Virol. 1991 Sep;65(9):4985–4990. [PMC free article] [PubMed]
  • Bomsztyk K, Toivola B, Emery DW, Rooney JW, Dower SK, Rachie NA, Sibley CH. Role of cAMP in interleukin-1-induced kappa light chain gene expression in murine B cell line. J Biol Chem. 1990 Jun 5;265(16):9413–9417. [PubMed]
  • Scheinman RI, Beg AA, Baldwin AS., Jr NF-kappa B p100 (Lyt-10) is a component of H2TF1 and can function as an I kappa B-like molecule. Mol Cell Biol. 1993 Oct;13(10):6089–6101. [PMC free article] [PubMed]
  • Cromartie WJ, Craddock JG, Schwab JH, Anderle SK, Yang CH. Arthritis in rats after systemic injection of streptococcal cells or cell walls. J Exp Med. 1977 Dec 1;146(6):1585–1602. [PMC free article] [PubMed]
  • Morgan RA, Cornetta K, Anderson WF. Applications of the polymerase chain reaction in retroviral-mediated gene transfer and the analysis of gene-marked human TIL cells. Hum Gene Ther. 1990 Summer;1(2):135–149. [PubMed]
  • Esser RE, Stimpson SA, Cromartie WJ, Schwab JH. Reactivation of streptococcal cell wall-induced arthritis by homologous and heterologous cell wall polymers. Arthritis Rheum. 1985 Dec;28(12):1402–1411. [PubMed]
  • Iwasaki T, Sims JE, Grabstein K, Dower SK, Rachie N, Bomsztyk K. Comparison of IL-1 alpha effectiveness in activating murine pre-B and T cell lines. Cytokine. 1993 Sep;5(5):416–426. [PubMed]
  • Baeuerle PA, Henkel T. Function and activation of NF-kappa B in the immune system. Annu Rev Immunol. 1994;12:141–179. [PubMed]
  • Stimpson SA, Dalldorf FG, Otterness IG, Schwab JH. Exacerbation of arthritis by IL-1 in rat joints previously injured by peptidoglycan-polysaccharide. J Immunol. 1988 May 1;140(9):2964–2969. [PubMed]
  • Granowitz EV, Porat R, Mier JW, Pribble JP, Stiles DM, Bloedow DC, Catalano MA, Wolff SM, Dinarello CA. Pharmacokinetics, safety and immunomodulatory effects of human recombinant interleukin-1 receptor antagonist in healthy humans. Cytokine. 1992 Sep;4(5):353–360. [PubMed]

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