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Targeting cytokines beyond tumor necrosis factor-α and interleukin-1 in rheumatoid arthritis

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Abstract

Targeting tumor necrosis factor-α has proven of considerable value in treatment for rheumatoid arthritis, with substantial benefits achieved in a proportion of treated patients. However, a significant number of patients do not achieve sufficient improvement and as a result there remains considerable unmet clinical need. A number of cytokines have recently been described with proinflammatory activity in rheumatoid arthritis synovitis, including interleukin (IL)-6, IL-12, IL-15, and IL-18. We review recent data that support the notion that some or all of these moieties offer therapeutic potential. The possibility that some may be useful in partial responders to tumor necrosis factor blocking agents or in synergy with the latter is discussed.

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References and Recommended Reading

  1. Taylor PC, Williams RO, Maini RN: Immunotherapy for rheumatoid arthritis. Curr Opin Immunol 2001, 13:611–616.

    Article  PubMed  CAS  Google Scholar 

  2. Klareskog L, van der Heijde D, de Jager JP, et al.: Therapeutic effect of the combination of etanercept and methotrexate compared with each treatment alone in patients with rheumatoid arthritis: double-blind randomized controlled trial. Lancet 2004, 363:675–681. An important paper showing the benefit of TNF blockade and synergy with methotrexate. Targeting multiple pathways within the joint would seem reasonable based on these observations.

    Article  PubMed  CAS  Google Scholar 

  3. Nishimoto N, Kishimoto T, Yoshizaki K: Anti-interleukin 6 receptor antibody treatment in rheumatic disease. Ann Rheum Dis 2000, 59:21–27. A comprehensive review of the rationale for IL-6 targeting human disease states.

    Article  Google Scholar 

  4. Alonzi T, Fattori E, Lazzaro D, et al.: Interleukin 6 is required for the development of collagen-induced arthritis. J Exp Med 1998, 187:461–468.

    Article  PubMed  CAS  Google Scholar 

  5. Takagi N, Mihara M, Moriya Y, et al.: Blockage of interleukin-6 receptor ameliorates joint disease in murine collageninduced arthritis. Arthritis Rheum 1998, 41:2117–2121.

    Article  PubMed  CAS  Google Scholar 

  6. Mihara M, Kotoh M, Nishimoto N, et al.: Humanized antibody to human interleukin-6 receptor inhibits the development of collagen arthritis in cynomolgus monkeys. Clin Immunol 2001, 98:319–326.

    Article  PubMed  CAS  Google Scholar 

  7. Choy EH, Isenberg DA, Garrood T, et al.: Therapeutic benefit of blocking interleukin-6 activity with an anti-interleukin-6 receptor monoclonal antibody in rheumatoid arthritis: a randomized, double-blind, placebo-controlled, dose-escalation trial. Arthritis Rheum 2002, 46:3143–3150.

    Article  PubMed  CAS  Google Scholar 

  8. Nakahara H, Song J, Sugimoto M, et al.: Anti-interleukin-6 receptor antibody therapy reduces vascular endothelial growth factor production in rheumatoid arthritis. Arthritis Rheum 2003, 48:1521–1529.

    Article  PubMed  CAS  Google Scholar 

  9. Nishimoto N, Yoshizaki K, Miyasaka N, et al.: Treatment of rheumatoid arthritis with humanized anti-interleukin-6 receptor antibody: a multicenter, double-blind, placebo-controlled trial. Arthritis Rheum 2004, 50:1761–1769. This is the pivotal phase II study that shows benefit against placebo for IL-6 blockade in RA.

    Article  PubMed  CAS  Google Scholar 

  10. Yokota S: Interleukin 6 as a therapeutic target in systemiconset juvenile idiopathic arthritis. Curr Opin Rheumatol 2003, 15:581–586.

    Article  PubMed  CAS  Google Scholar 

  11. Feldmann M, Brennan FM, Maini RN: Role of cytokines in rheumatoid arthritis. Annu Rev Immunol 1996, 14:397–440.

    Article  PubMed  CAS  Google Scholar 

  12. Miossec P: Are T cells in rheumatoid synovium aggressors or bystanders? Curr Opin Rheumatol 2000, 12:181–185.

    Article  PubMed  CAS  Google Scholar 

  13. Morita Y, Yamamura M, Nishida K, et al.: Expression of interleukin-12 in synovial tissue from patients with rheumatoid arthritis. Arthritis Rheum 1998, 41:306–314.

    Article  PubMed  CAS  Google Scholar 

  14. Hessian PA, Highton J, Kean A, et al.: Cytokine profile of the rheumatoid nodule suggests that it is a Th1 granuloma. Arthritis Rheum 2003, 48:334–338.

    Article  PubMed  CAS  Google Scholar 

  15. Gracie JA, Forsey RJ, Chan WL, et al.: A proinflammatory role for IL-18 in rheumatoid arthritis. J Clin Invest 1999, 104:1393–1401. This is the first report of IL-18 expression in RA synovial tissue. This report clearly defines the potential for synergistic function of IL-12 with IL-15 and IL-18 in synovitis.

    PubMed  CAS  Google Scholar 

  16. Hess H, Gately MK, Rude E, et al.: High doses of interleukin-12 inhibit the development of joint disease in DBA/1 mice immunized with type II collagen in complete Freund’s adjuvant. Eur J Immunol 1996, 26:187–191.

    Article  PubMed  CAS  Google Scholar 

  17. Leung BP, McInnes IB, Esfandiari E, et al.: Combined effects of IL-12 and IL-18 on the induction of collagen-induced arthritis. J Immunol 2000, 164:6495–6502.

    PubMed  CAS  Google Scholar 

  18. Malfait AM, Butler DM, Presky DH, et al.: Blockade of IL-12 during the induction of collagen-induced arthritis (CIA) markedly attenuates the severity of the arthritis. Clin Exp Immunol 1998, 111:377–383.

    Article  PubMed  CAS  Google Scholar 

  19. Joosten LA, Lubberts E, Helsen MM, van den Berg WB: Dual role of IL-12 in early and late stages of murine collagen type II arthritis. J Immunol 1997, 159:4094–4102.

    PubMed  CAS  Google Scholar 

  20. Butler DM, Malfait AM, Maini RN, et al.: Anti-IL-12 and anti-TNF antibodies synergistically suppress the progression of murine collagen-induced arthritis. Eur J Immunol 1999, 29:2205–2212.

    Article  PubMed  CAS  Google Scholar 

  21. Joosten LA, Heuvelmans-Jacobs M, Lubberts E, et al.: Local interleukin-12 gene transfer promotes conversion of an acute arthritis to a chronic destructive arthritis. Arthritis Rheum 2002, 46:1379–1389.

    Article  PubMed  CAS  Google Scholar 

  22. Finnegan A, Grusby MJ, Kaplan CD, et al.: IL-4 and IL-12 regulate proteoglycan-induced arthritis through Stat-dependent mechanisms. J Immunol 2002, 169:3345–3352.

    PubMed  CAS  Google Scholar 

  23. Frucht DM, Aringer M, Galon J, et al.: Stat4 is expressed in activated peripheral blood monocytes, dendritic cells, and macrophages at sites of Th1-mediated inflammation. J Immunol 2000, 164:4659–4664.

    PubMed  CAS  Google Scholar 

  24. Murphy CA, Langrish CL, Chen Y, et al.: Divergent pro- and antiinflammatory roles for IL-23 and IL-12 in joint autoimmune inflammation. J Exp Med 2003, 198:1951–1957. This is the first report to clarify the relationship of IL-12 and IL-23 and raises the possibility that IL-23 may offer therapeutic potential.

    Article  PubMed  CAS  Google Scholar 

  25. Sigidin YA, Loukina GV, Skurkovich B, Skurkovich S: Randomized, double-blind trial of anti-interferon-gamma antibodies in rheumatoid arthritis. Scand J Rheumatol 2001, 30:203–207.

    Article  PubMed  CAS  Google Scholar 

  26. Grabstein KH, Eisenman J, Shanebeck K, et al.: Cloning of a T cell growth factor that interacts with the beta chain of the interleukin-2 receptor. Science 1994, 264:965–968.

    Article  PubMed  CAS  Google Scholar 

  27. Waldmann TA, Tagaya Y: The multifaceted regulation of interleukin-15 expression and the role of this cytokine in nk cell differentiation and host response to intracellular pathogens. Annu Rev Immunol 1999, 17:19–49. An excellent review of the biology of IL-15 in health and disease. This contains numerous source papers that have lead the field.

    Article  PubMed  CAS  Google Scholar 

  28. Dubois S, Mariner J, Waldmann TA, Tagaya Y: IL-15Ralpha recycles and presents IL-15 In trans to neighboring cells. Immunity 2002, 17:537–547.

    Article  PubMed  CAS  Google Scholar 

  29. Giri JG, Kumaki S, Ahdieh M, et al.: Identification and cloning of a novel IL-15 binding protein that is structurally related to the alpha chain of the IL-2 receptor. Embo J 1995, 14:3654–3663.

    PubMed  CAS  Google Scholar 

  30. Waldmann T, Tagaya Y, Bamford R: Interleukin-2, interleukin-15, and their receptors. Int Rev Immunol 1998, 16:205–226.

    PubMed  CAS  Google Scholar 

  31. McInnes IB, Gracie JA, Harnett M, et al.: New strategies to control inflammatory synovitis: interleukin 15 and beyond. Ann Rheum Dis 2003, 62(Suppl 2):51–54.

    Google Scholar 

  32. McInnes IB, Leung BP, Sturrock RD, et al.: Interleukin-15 mediates T cell-dependent regulation of tumor necrosis factoralpha production in rheumatoid arthritis. Nat Med 1997, 3:189–195. This is the first report to define the bioactivity of IL-15 in RA synovitis.

    Article  PubMed  CAS  Google Scholar 

  33. Gonzalez-Alvaro I, Ortiz AM, Garcia-Vicuna R, et al.: Increased serum levels of interleukin-15 in rheumatoid arthritis with long-term disease. Clin Exp Rheumatol 2003, 21:639–642.

    PubMed  CAS  Google Scholar 

  34. Smolewska E, Brozik H, Smolewski P, et al.: Apoptosis of peripheral blood lymphocytes in patients with juvenile idiopathic arthritis. Ann Rheum Dis 2003, 62:761–763.

    Article  PubMed  CAS  Google Scholar 

  35. McInnes IB, Leung BP, Liew FY: Cell-cell interactions in synovitis. Interactions between T lymphocytes and synovial cells. Arthritis Res 2000, 2:374–378.

    Article  PubMed  CAS  Google Scholar 

  36. Cho ML, Yoon CH, Hwang SY, et al.: Effector function of type II collagen-stimulated T cells from rheumatoid arthritis patients: cross-talk between T cells and synovial fibroblasts. Arthritis Rheum 2004, 50:776–784.

    Article  PubMed  CAS  Google Scholar 

  37. Groh V, Bruhl A, El-Gabalawy H, et al.: Stimulation of T cell autoreactivity by anomalous expression of NKG2D and its MIC ligands in rheumatoid arthritis. Proc Natl Acad Sci U S A 2003, 100:9452–9457.

    Article  PubMed  CAS  Google Scholar 

  38. Wang CR, Liu MF: Regulation of CCR5 expression and MIP-1alpha production in CD4+ T cells from patients with rheumatoid arthritis. Clin Exp Immunol 2003, 132:371–378.

    Article  PubMed  CAS  Google Scholar 

  39. Ruchatz H, Leung BP, Wei XQ, et al.: Soluble IL-15 receptor alpha-chain administration prevents murine collageninduced arthritis: a role for IL-15 in development of antigeninduced immunopathology. J Immunol 1998, 160:5654–5660.

    PubMed  CAS  Google Scholar 

  40. Kim YS, Maslinski W, Zheng XX, et al.: Targeting the IL-15 receptor with an antagonist IL-15 mutant/Fc gamma2a protein blocks delayed-type hypersensitivity. J Immunol 1998, 160:5742–5748.

    PubMed  CAS  Google Scholar 

  41. Ferrari-Lacraz S, Zheng XX, Kim YS, et al.: An antagonist IL-15/ Fc protein prevents costimulation blockade-resistant rejection. J Immunol 2001, 167:3478–3485. An interesting paper that shows the potential for an IL-15 mutant fusion protein as an IL-15 antagonist.

    PubMed  CAS  Google Scholar 

  42. Nakamura K, Okamura H, Wada M, et al.: Endotoxin-induced serum factor that stimulates gamma interferon production. Infect Immun 1989, 57:590–595.

    PubMed  CAS  Google Scholar 

  43. Gracie JA, Robertson SE, McInnes IB: Interleukin-18. J Leukoc Biol 2003, 73:213–224.

    Article  PubMed  CAS  Google Scholar 

  44. Ghayur T, Banerjee S, Hugunin M, et al.: Caspase-1 processes IFN-gamma-inducing factor and regulates LPS-induced IFNgamma production. Nature 1997, 386:619–623.

    Article  PubMed  CAS  Google Scholar 

  45. Gu Y, Kuida K, Tsutsui H, et al.: Activation of interferongamma inducing factor mediated by interleukin-1beta converting enzyme. Science 1997, 275:206–209.

    Article  PubMed  CAS  Google Scholar 

  46. Sugawara S, Uehara A, Nochi T, et al.: Neutrophil proteinase 3-mediated induction of bioactive IL-18 secretion by human oral epithelial cells. J Immunol 2001, 167:6568–6575.

    PubMed  CAS  Google Scholar 

  47. Dinarello CA, Fantuzzi G: Interleukin-18 and host defense against infection. J Infect Dis 2003, 187(Suppl 2):S370–384.

    Article  PubMed  CAS  Google Scholar 

  48. Mehta VB, Hart J, Wewers MD: ATP-stimulated release of interleukin (IL)-1beta and IL-18 requires priming by lipopolysaccharide and is independent of caspase-1 cleavage. J Biol Chem 2001, 276:3820–3826.

    Article  PubMed  CAS  Google Scholar 

  49. Torigoe K, Ushio S, Okura T, et al.: Purification and characterization of the human interleukin-18 receptor. J Biol Chem 1997, 272:25737–25742.

    Article  PubMed  CAS  Google Scholar 

  50. Born TL, Thomassen E, Bird TA, Sims JE: Cloning of a novel receptor subunit, AcPL, required for interleukin-18 signaling. J Biol Chem 1998, 273:29445–29450.

    Article  PubMed  CAS  Google Scholar 

  51. Adachi O, Kawai T, Takeda K, et al.: Targeted disruption of the MyD88 gene results in loss of IL-1- and IL-18-mediated function. Immunity 1998, 9:143–150.

    Article  PubMed  CAS  Google Scholar 

  52. Novick D, Kim SH, Fantuzzi G, et al.: Interleukin-18 binding protein: a novel modulator of the Th1 cytokine response. Immunity 1999, 10:127–136. This is the first paper to describe the existence and biology of IL-18BP. This in turn has lead to the development of a novel IL-8 targeting strategy in current clinical trials.

    Article  PubMed  CAS  Google Scholar 

  53. Pan G, Risser P, Mao W, et al.: IL-1H, an interleukin 1-related protein that binds IL-18 receptor/IL-1Rrp. Cytokine 2001, 13:1–7.

    Article  PubMed  CAS  Google Scholar 

  54. Yamamura M, Kawashima M, Taniai M, et al.: Interferongamma-inducing activity of interleukin-18 in the joint with rheumatoid arthritis. Arthritis Rheum 2001, 44:275–285.

    Article  PubMed  CAS  Google Scholar 

  55. Kawashima M, Miossec P: Heterogeneity of response of rheumatoid synovium cell subsets to interleukin-18 in relation to differential interleukin-18 receptor expression. Arthritis Rheum 2003, 48:631–637.

    Article  PubMed  CAS  Google Scholar 

  56. Lubberts E, van den Berg WB: Potential of modulatory cytokines in the rheumatoid arthritis process. Drug News Perspect 2001, 14:517–522.

    Article  PubMed  CAS  Google Scholar 

  57. Leung BP, Culshaw S, Gracie JA, et al.: A role for IL-18 in neutrophil activation. J Immunol 2001, 167:2879–2886.

    PubMed  CAS  Google Scholar 

  58. Horwood NJ, Udagawa N, Elliott J, et al.: Interleukin 18 inhibits osteoclast formation via T cell production of granulocyte macrophage colony-stimulating factor. J Clin Invest 1998, 101:595–603.

    Article  PubMed  CAS  Google Scholar 

  59. Wei XQ, Leung BP, Arthur HM, et al.: Reduced incidence and severity of collagen-induced arthritis in mice lacking IL-18. J Immunol 2001, 166:517–521.

    PubMed  CAS  Google Scholar 

  60. Plater-Zyberk C, Joosten LA, Helsen MM, et al.: Therapeutic effect of neutralizing endogenous IL-18 activity in the collagen-induced model of arthritis. J Clin Invest 2001, 108:1825–1832. This paper gives powerful proof of concept that IL-18 targeting can be effective in ameliorating synovitis in vivo.

    Article  PubMed  CAS  Google Scholar 

  61. Smeets RL, Van De Loo FA, Arntz OJ, et al.: Adenoviral delivery of IL-18 binding protein C ameliorates collagen-induced arthritis in mice. Gene Ther 2003, 10:1004–1011.

    Article  PubMed  CAS  Google Scholar 

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McInnes, I.B., Gracie, J.A. Targeting cytokines beyond tumor necrosis factor-α and interleukin-1 in rheumatoid arthritis. Current Science Inc 9, 405–411 (2005). https://doi.org/10.1007/s11916-005-0020-9

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