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Co-stimulatory pathways in the therapy of rheumatoid arthritis

  • Chapter
New Therapeutic Targets in Rheumatoid Arthritis

Part of the book series: Progress in Inflammation Research ((PIR))

Abstract

Although T lymphocytes are widely recognized as important effector cells in the immunopathogenesis of rheumatoid arthritis (RA), therapies targeting T cell populations have not been clinically successful, largely due to the toxicity associated with nonspecific T cell depletion. An alternative approach involves targeting T cell activation, a process that requires two distinct signals. In addition to the cognate interaction between the T cell receptor on T cells and antigen bound to the major histocompatibility complex on the antigen-presenting cell (APC), a second, co-stimulatory, signal is required for T cell activation. Therapies targeting co-stimulatory pathways, aimed at modifying the activation of T cells, rather than reducing their absolute numbers, may be an effective alternative to T cell depletion in RA and other rheumatic diseases. One such treatment, abatacept (CTLA4Ig), a fusion protein combining cytotoxic T lymphocyte antigen 4 (CTLA4) and a portion of the Fc domain of human IgG1, has been approved in the United States and the European Union for the treatment of RA. Abatacept may modulate the T cell or the APC to produce several different outcomes within the joint, including down-regulation of T cell activation, stimulation of T cell apoptosis, or possibly modulation of T regulatory cell activity. In large, controlled trials in patients with RA with an inadequate response to either methotrexate or TNF antagonists, abatacept effectively reduced disease activity. In the methotrexate-inadequate responder population, radiographic progression was slowed when compared to continued treatment with methotrexate alone. The safety profile of this therapy is similar to that of other biological response modifiers, with infection being the most concerning treatment-emergent adverse event. Additional co-stimulatory pathways may offer attractive targets in RA and other immune-mediated diseases, although, to date, none has had the clinical success of abatacept and the related CTLA4Ig fusion protein, belatacept.

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References

  1. Keir ME, Sharpe AH (2005) The B7/CD28 costimulatory family in autoimmunity. Immunol Rev 204: 128–43

    Article  PubMed  CAS  Google Scholar 

  2. De Smedt T, Pajak B, Muraille E, Lespagnard L, Heinen E, De Baetselier P et al (1996) Regulation of dendritic cell numbers and maturation by lipopolysaccharide in vivo. J Exp Med 184: 1413–24

    Article  PubMed  Google Scholar 

  3. van Amelsfort JM, van Roon JA, Noordegraaf M, Jacobs KM, Bijlsma JW, Lafeber FP et al (2007) Proinflammatory mediator-induced reversal of CD4+,CD25+ regulatory T cell-mediated suppression in rheumatoid arthritis. Arthritis Rheum 56: 732–42

    Article  PubMed  CAS  Google Scholar 

  4. Verwilghen J, Lovis R, De Boer M, Linsley PS, Haines GK, Koch AE et al (1994) Expression of functional B7 and CTLA4 on rheumatoid synovial T cells. J Immunol 153: 1378–85

    PubMed  CAS  Google Scholar 

  5. Karandikar NJ, Vanderlugt CL, Walunas TL, Miller SD, Bluestone JA (1996) CTLA-4: A negative regulator of autoimmune disease. J Exp Med 184: 783–8

    Article  PubMed  CAS  Google Scholar 

  6. Walunas TL, Bakker CY, Bluestone JA (1996) CTLA-4 ligation blocks CD28-dependent T cell activation. J Exp Med 183: 2541–50

    Article  PubMed  CAS  Google Scholar 

  7. Peach RJ, Bajorath J, Brady W, Leytze G, Greene J, Naemura J et al (1994) Complementarity determining region 1 (CDR1)-and CDR3-analogous regions in CTLA-4 and CD28 determine the binding to B7-1. J Exp Med 180: 2049–58

    Article  PubMed  CAS  Google Scholar 

  8. Egen JG, Allison JP (2002) Cytotoxic T lymphocyte antigen-4 accumulation in the immunological synapse is regulated by TCR signal strength. Immunity 16: 23–35

    Article  PubMed  CAS  Google Scholar 

  9. Grohmann U, Orabona C, Fallarino F, Vacca C, Calcinaro F, Falorni A et al (2002) CTLA-4-Ig regulates tryptophan catabolism in vivo. Nat Immunol 3: 1097–101

    Article  PubMed  CAS  Google Scholar 

  10. Lee GK, Park HJ, Macleod M, Chandler P, Munn DH, Mellor AL (2002) Tryptophan deprivation sensitizes activated T cells to apoptosis prior to cell division. Immunology 107: 452–60

    Article  PubMed  CAS  Google Scholar 

  11. Fontenot JD, Gavin MA, Rudensky AY (2003) Foxp3 programs the development and function of CD4+CD25+ regulatory T cells. Nat Immunol 4: 330–6

    Article  PubMed  CAS  Google Scholar 

  12. Tang Q, Henriksen KJ, Boden EK, Tooley AJ, Ye J, Subudhi SK et al (2003) Cutting edge: CD28 controls peripheral homeostasis of CD4+CD25+ regulatory T cells. J Immunol 171: 3348–52

    PubMed  CAS  Google Scholar 

  13. van Amelsfort JM, Jacobs KM, Bijlsma JW, Lafeber FP, Taams LS (2004) CD4(+) CD25(+) regulatory T cells in rheumatoid arthritis: Differences in the presence, phenotype, and function between peripheral blood and synovial fluid. Arthritis Rheum 50: 2775–85

    Article  PubMed  Google Scholar 

  14. Liang L, Sha WC (2002) The right place at the right time: Novel B7 family members regulate effector T cell responses. Curr Opin Immunol 14: 384–90

    Article  PubMed  CAS  Google Scholar 

  15. Ruth JH, Rottman JB, Kingsbury GA, Coyle AJ, Haines GK 3rd, Pope RM et al (2007) ICOS and B7 costimulatory molecule expression identifies activated cellular subsets in rheumatoid arthritis. Cytometry A 71: 317–26

    PubMed  Google Scholar 

  16. Nurieva RI, Treuting P, Duong J, Flavell RA, Dong C (2003) Inducible costimulator is essential for collagen-induced arthritis. J Clin Invest 111: 701–6

    Article  PubMed  CAS  Google Scholar 

  17. Iwai H, Kozono Y, Hirose S, Akiba H, Yagita H, Okumura K et al (2002) Amelioration of collagen-induced arthritis by blockade of inducible costimulator-B7 homologous protein costimulation. J Immunol 169: 4332–9

    PubMed  CAS  Google Scholar 

  18. Wan B, Nie H, Liu A, Feng G, He D, Xu R et al (2006) Aberrant regulation of synovial T cell activation by soluble costimulatory molecules in rheumatoid arthritis. J Immunol 177: 8844–50

    PubMed  CAS  Google Scholar 

  19. Liu EH, Siegel RM, Harlan DM, O’Shea JJ (2007) T cell-directed therapies: Lessons learned and future prospects. Nat Immunol 8: 25–30

    Article  PubMed  CAS  Google Scholar 

  20. Liu MF, Chao SC, Wang CR, Lei HY (2001) Expression of CD40 and CD40 ligand among cell populations within rheumatoid synovial compartment. Autoimmunity 34: 107–13

    Article  PubMed  CAS  Google Scholar 

  21. Moreland LW, Alten R, Van den Bosch F, Appelboom T, Leon M, Emery P et al (2002) Costimulatory blockade in patients with rheumatoid arthritis: A pilot, dose-finding, double-blind, placebo-controlled clinical trial evaluating CTLA-4Ig and LEA29Y eightyfive days after the first infusion. Arthritis Rheum 46: 1470–9

    Article  PubMed  CAS  Google Scholar 

  22. Knoerzer DB, Karr RW, Schwartz BD, Mengle-Gaw LJ (1995) Collagen-induced arthritis in the BB rat. Prevention of disease by treatment with CTLA-4-Ig. J Clin Invest 96: 987–93

    Article  PubMed  CAS  Google Scholar 

  23. Tada Y, Nagasawa K, Ho A, Morito F, Ushiyama O, Suzuki N et al (1999) CD28-deficient mice are highly resistant to collagen-induced arthritis. J Immunol 162: 203–8

    PubMed  CAS  Google Scholar 

  24. Vincenti F, Larsen C, Durrbach A, Wekerle T, Nashan B, Blancho G et al (2005) Costimulation blockade with belatacept in renal transplantation. N Engl J Med 353: 770–81

    Article  PubMed  CAS  Google Scholar 

  25. Kremer JM, Dougados M, Emery P, Durez P, Sibilia J, Shergy W et al (2005) Treatment of rheumatoid arthritis with the selective costimulation modulator abatacept: Twelve month results of a Phase IIb, double-blind, randomized, placebo-controlled trial. Arthritis Rheum 52: 2263–71

    Article  PubMed  CAS  Google Scholar 

  26. Kremer JM, Genant HK, Moreland LW, Russell AS, Emery P, Abud-Mendoza C et al (2006) Effects of abatacept in patients with methotrexate-resistant active rheumatoid arthritis: A randomized trial. Ann Inter Med 144: 865–76

    CAS  Google Scholar 

  27. Kremer JM, Westhovens R, Leon M, Di Giorgio E, Alten R, Steinfeld S et al (2003) Treatment of rheumatoid arthritis by selective inhibition of T-cell activation with fusion protein CTLA4Ig. N Engl J Med 349: 1907–15

    Article  PubMed  CAS  Google Scholar 

  28. Emery P, Kosinski M, Li T, Martin M, Williams GR, Becker JC et al (2006) Treatment of rheumatoid arthritis patients with abatacept and methotrexate significantly improved health-related quality of life. J Rheumatol 33: 681–9

    PubMed  CAS  Google Scholar 

  29. Norman GR, Sloan JA, Wyrwich KW (2003) Interpretation of changes in health-related quality of life: The remarkable universality of half a standard deviation. Med Care 41: 582–92

    Article  PubMed  Google Scholar 

  30. Weisman MH, Durez P, Hallegua D, Aranda R, Becker JC, Nuamah I et al (2006) Reduction of inflammatory biomarker response by abatacept in treatment of rheumatoid arthritis. J Rheumatol 33: 2162–6

    PubMed  CAS  Google Scholar 

  31. Russell AS, Wallenstein GV, Li T, Martin MC, Maclean R, Blaisdell B et al (2007) Abatacept improves both the physical and mental health of patients with rheumatoid arthritis who have inadequate response to methotrexate treatment. Ann Rheum Dis 66: 189–94

    Article  PubMed  CAS  Google Scholar 

  32. Genovese MC, Becker JC, Schiff M, Luggen M, Sherrer Y, Kremer J et al (2005) Abatacept for rheumatoid arthritis refractory to tumor necrosis factor alpha inhibition. N Engl J Med 353: 1114–23

    Article  PubMed  CAS  Google Scholar 

  33. Westhovens R, Cole JC, Li T, Martin M, Maclean R, Lin P et al (2006) Improved healthrelated quality of life for rheumatoid arthritis patients treated with abatacept who have inadequate response to anti-TNF therapy in a double-blind, placebo-controlled, multicentre randomized clinical trial. Rheumatology 45: 1238–46

    Article  PubMed  CAS  Google Scholar 

  34. Weinblatt M, Schiff M, Goldman A, Kremer J, Luggen M, Li T et al (2007) Selective costimulation modulation using abatacept in patients with active rheumatoid arthritis while receiving etanercept: A randomised clinical trial. Ann Rheum Dis 66: 228–34

    Article  PubMed  CAS  Google Scholar 

  35. Weinblatt M, Combe B, Covucci A, Aranda R, Becker JC, Keystone E (2006) Safety of the selective costimulation modulator abatacept in rheumatoid arthritis patients receiving background biologic and nonbiologic disease-modifying antirheumatic drugs: A one-year randomized, placebo-controlled study. Arthritis Rheum 54: 2807–16

    Article  PubMed  CAS  Google Scholar 

  36. Moreland L, Kaine J, Espinoza L, McCann T, Aranda R, Becker JC et al (2005) Safety of abatacept in rheumatoid arthritis patients in five double-blind, placebo-controlled trials. American College of Rheumatology Annual Meeting, Abstract 886

    Google Scholar 

  37. Ruperto N, Lovell DJ, Quartier P, Paz E, Rubio-Pérez NE, Silva CA et al (2008) Abatacept in children with juvenile idiopathic arthritis: a randomised, double-blind, placebocontrolled withdrawal trial. Lancet 372: 383–391

    Article  PubMed  CAS  Google Scholar 

  38. Schiff M, Keiserman M, Codding C, Songcharoen S, Berman A, Nayiager S et al (2008) Efficacy and safety of abatacept or infliximab vs placebo in ATTET: a phase III, multicentre, randomised, double-blind, placebo-controlled study in patients with rheumatoid arthritis and an inadequate response to methotrexate. Ann Rheum Dis 67: 1096–1103

    Article  PubMed  CAS  Google Scholar 

  39. Nadkarni S, Mauri C, Ehrenstein MR (2007) Anti-TNF-alpha therapy induces a distinct regulatory T cell population in patients with rheumatoid arthritis via TGF-beta. J Exp Med 204: 33–9

    Article  PubMed  CAS  Google Scholar 

  40. Ehrenstein MR, Evans JG, Singh A, Moore S, Warnes G, Isenberg DA et al (2004) Compromised function of regulatory T cells in rheumatoid arthritis and reversal by anti-TNFalpha therapy. J Exp Med 200: 277–85

    Article  PubMed  CAS  Google Scholar 

  41. Merill JT, Burgos-Vargas R, Westhovens R, Chalmers A, D’Cruz D, Wallace D et al (2008) The efficacy and safety of abatacept in SLE: Result of a 12-month exploratory study. American College of Rheumatology Annual Meeting, Abstract L 15

    Google Scholar 

  42. Daoussis D, Andonopoulos AP, Liossis SN (2004) Targeting CD40L: A promising therapeutic approach. Clin Diagn Lab Immunol 11: 635–41

    PubMed  CAS  Google Scholar 

  43. Toubi E, Shoenfeld Y (2004) The role of CD40-CD154 interactions in autoimmunity and the benefit of disrupting this pathway. Autoimmunity 37: 457–64

    Article  PubMed  CAS  Google Scholar 

  44. Boumpas DT, Furie R, Manzi S, Illei GG, Wallace DJ, Balow JE et al (2003) A short course of BG9588 (anti-CD40 ligand antibody) improves serologic activity and decreases hematuria in patients with proliferative lupus glomerulonephritis. Arthritis Rheum 48: 719–27

    Article  PubMed  CAS  Google Scholar 

  45. Kalunian KC, Davis JC Jr, Merrill JT, Totoritis MC, Wofsy D (2002) Treatment of systemic lupus erythematosus by inhibition of T cell costimulation with anti-CD154: A randomized, double-blind, placebo-controlled trial. Arthritis Rheum 46: 3251–8

    Article  PubMed  CAS  Google Scholar 

  46. Rodriguez-Palmero M, Franch A, Castell M, Pelegri C, Perez-Cano FJ, Kleinschnitz C et al. (2006) Effective treatment of adjuvant arthritis with a stimulatory CD28-specific monoclonal antibody. J Rheumatol 33: 110–8

    PubMed  CAS  Google Scholar 

  47. Suntharalingam G, Perry MR, Ward S, Brett SJ, Castello-Cortes A, Brunner MD et al (2006) Cytokine storm in a phase 1 trial of the anti-CD28 monoclonal antibody TGN1412. N Engl J Med 355: 1018–28

    Article  PubMed  CAS  Google Scholar 

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Authors and Affiliations

  1. Division of Rheumatology, Northwestern University Feinberg School of Medicine, McGaw M300, 240 E. Huron Street, Chicago, IL, 60611, USA

    Eric M. Ruderman & Richard M. Pope

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  1. Eric M. Ruderman
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  2. Richard M. Pope
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Editors and Affiliations

  1. Division of Clinical Immunology and Rheumatology EULAR & FOCIS Center of Excellence Academic Medical Center, University of Amsterdam, Meibergdreef 9, Room F4-218, 1105, AZ Amsterdam, The Netherlands

    Paul-Peter Tak

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Ruderman, E.M., Pope, R.M. (2009). Co-stimulatory pathways in the therapy of rheumatoid arthritis. In: Tak, PP. (eds) New Therapeutic Targets in Rheumatoid Arthritis. Progress in Inflammation Research. Birkhäuser Basel. https://doi.org/10.1007/978-3-7643-8238-4_2

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  • DOI: https://doi.org/10.1007/978-3-7643-8238-4_2

  • Publisher Name: Birkhäuser Basel

  • Print ISBN: 978-3-7643-8237-7

  • Online ISBN: 978-3-7643-8238-4

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