Journal of Clinical Immunology

, Volume 27, Issue 6, pp 580–588 | Cite as

The Effect of Blockade of Tumor Necrosis Factor α on VLA-1+T-Cells in Rheumatoid Arthritis Patients

  • Ilan Bank
  • Shomron Ben-Horin
  • Itamar Goldstein
  • Alexander Koltakov
  • Pnina Langevitz
  • Michael Ehrenfeld
  • Esther Rosenthal
  • Hanan Gur


The α1β1 integrin, very late antigen (VLA)-1, characterizes collagen adherent interferon (IFN) γ producing memory T cells in inflamed synovium. We now report that the mean percentage of VLA-1+ T cells is significantly lower among peripheral blood mononuclear cells of rheumatoid patients responsive to antitumor necrosis factor (TNF) α therapy than of those with active disease not receiving therapy. Neutralization of TNFα during in vitro polyclonal activation of VLA-1− T cells reduced differentiation to expression of VLA-1 and inhibited secretion of IFNγ, but did not affect integrin expression on in vivo differentiated VLA-1+ T cells. Moreover, synovial fluids of patients relapsing during and after therapy were enriched in VLA-1+ T cells and lines derived from VLA-1+ T cells in peripheral blood of treated patients retained collagen binding and secreted IFN γ. Thus, whereas therapy decreases VLA-1+ T cells in rheumatoid arthritis patients, a subset is resistant and contributes to residual and recurring inflammation.


T cells VLA-1 integrins collagen type IV CD45RO memory T cells arthritis 



This work was supported in part by an investigator initiated non restricted grant from Biogen Idec to I. B.


  1. 1.
    Bank I, Hemler M, Brenner MB, Cohen D, Levy V, Belko J, Crouse C, Chess L. A novel monoclonal antibody, 1B3.1, binds to a new epitope of the VLA-1 molecule. Cell Immunol 1989;122:416–23.PubMedCrossRefGoogle Scholar
  2. 2.
    Hemler ME, Jacobson JG, Brenner MB, Mann D, Strominger JL. VLA-1: a T cell surface antigen which defines a novel late stage of human T cell activation. Eur J Immunol 1985;15:502–8.PubMedCrossRefGoogle Scholar
  3. 3.
    Bank I, Koltakov A, Goldstein I, Chess L. Lymphocytes expressing alpha1beta1 integrin (Very Late Antigen-1) in peripheral blood of patients with arthritis are a subset of CD45RO(+) T-cells primed for rapid adhesion to collagen IV. Clin Immunol 2002;105:247–58.PubMedCrossRefGoogle Scholar
  4. 4.
    Goldstein I, Ben-Horin S, Li J, Bank I, Jiang H, Chess L. Expression of the alpha1beta1 integrin, VLA-1, marks a distinct subset of human CD4+memory T cells. J Clin Invest 2003;112:1444–54.PubMedCrossRefGoogle Scholar
  5. 5.
    Goldstein I, Ben-Horin S, Koltakov A, Chermoshnuk H, Polevoy V, Berkun Y, Amariglio N, Bank I. alpha1beta1 integrin+ and regulatory Foxp3+ T cells constitute two functionally distinct human CD4+T cell subsets oppositely modulated by TNFalpha blockade. J Immunol 2007;178:201–10.PubMedGoogle Scholar
  6. 6.
    Bank I, Roth D, Book M, Guterman A, Shnirrer I, Block R, Ehrenfeld M, Langevitz P, Brenner H, Pras M. Expression and functions of very late antigen 1 in inflammatory joint diseases.J Clin Immunol 1991;11:29–38.PubMedCrossRefGoogle Scholar
  7. 7.
    Hemler ME, Glass D, Coblyn JS, Jacobson JG. Very late activation antigens on rheumatoid synovial fluid T lymphocytes. Association with stages of T cell activation. J Clin Invest 1986;78:696–702.PubMedCrossRefGoogle Scholar
  8. 8.
    de Fougerolles A R, Sprague A G, Nickerson-Nutter CL, Chi-Rosso G, Rennert PD, Gardner H, Gotwals PJ, Lobb RR, Koteliansky VE. Regulation of inflammation by collagen-binding integrins alpha1beta1 and alpha2beta1 in models of hypersensitivity and arthritis. J Clin Invest 2000;105:721–729.PubMedGoogle Scholar
  9. 9.
    Feldmann M, Maini RN, Bondeson J, Taylor P, Foxwell BM, Brennan FM. Cytokine blockade in rheumatoid arthritis. Adv Exp Med Biol 2001;490:119–127.PubMedGoogle Scholar
  10. 10.
    Lipsky PE, van der Heijde DM, St Clair EW, Furst DE, Breedveld FC, Kalden JR, Smolen JS, Weisman M, Emery P, Feldmann M, Harriman GR, Maini RN. Infliximab and methotrexate in the treatment of rheumatoid arthritis. Anti-Tumor Necrosis Factor Trial in Rheumatoid Arthritis with Concomitant Therapy Study Group. N Engl J Med 2000;343:1594–1602.PubMedCrossRefGoogle Scholar
  11. 11.
    Cope AP, Liblau RS, Yang XD, Congia M, Laudanna C, Schreiber RD, Probert L, Kollias G, McDevitt HO. Chronic tumor necrosis factor alters T cell responses by attenuating T cell receptor signaling. J Exp Med 1997;185:1573–84.PubMedCrossRefGoogle Scholar
  12. 12.
    Scheurich P, Thoma B, Ucer U, Pfizenmaier K. Immunoregulatory activity of recombinant human tumor necrosis factor (TNF)-alpha: induction of TNF receptors on human T cells and TNF-alpha-mediated enhancement of T cell responses. J Immunol 1987;138:1786–90.PubMedGoogle Scholar
  13. 13.
    Arnett FC, Edworthy SM, Bloch DA, McShane DJ, Fries JF, Cooper NS, Healey LA, Kaplan SR, Liang MH, Luthra HS, et al. The American Rheumatism Association 1987 revised criteria for the classification of rheumatoid arthritis. Arthritis Rheum 1988;31:315–24.PubMedCrossRefGoogle Scholar
  14. 14.
    Bank I, Kapyla J, Grinbaum A, Doolman R, Bank J, Sela BA. Analysis of cell-free human alpha1 integrin with a monoclonal antibody to the I-domain: detection in ocular fluid and function as an adhesion substrate. Cell Adhes Commun 2001;8:113–123.Google Scholar
  15. 15.
    Bank I, Koltakov A, Nir-Glickman E, Goldstein I, Li J, Roitelman J, Chess L. Lovastatin and phospholipase Cgamma regulate constitutive and protein kinase C dependent integrin mediated interactions of human T-cells with collagen. Cell Immunol 2003;223:35–45.PubMedCrossRefGoogle Scholar
  16. 16.
    Krieglstein CF, Cerwinka WH, Sprague AG, Laroux FS, Grisham MB, Koteliansky VE, Senninger N, Granger DN, De Fougerolles AR. Collagen-binding integrin alpha(1)beta(1) regulates intestinal inflammation in experimental colitis. J Clin Invest 2002;110:1773–1782.PubMedCrossRefGoogle Scholar
  17. 17.
    Gailit J, Xu J, Bueller H, Clark RA. Platelet-derived growth factor and inflammatory cytokines have differential effects on the expression of integrins alpha 1 beta 1 and alpha 5 beta 1 by human dermal fibroblasts in vitro. J Cell Physiol 1996;169:281–289.PubMedCrossRefGoogle Scholar
  18. 18.
    Jin M, He S, Worpel V, Ryan SJ, Hinton DR. Promotion of adhesion and migration of RPE cells to provisional extracellular matrices by TNF-alpha. Invest Ophthalmol Vis Sci 2000;41:4324–4332.PubMedGoogle Scholar
  19. 19.
    van Valen F, Hanenberg H, Jurgens H. Expression of functional very late antigen-alpha 1, -alpha 2, -alpha 3 and-alpha 6 integrins on Ewing’s sarcoma and primitive peripheral neuroectodermal tumour cells and modulation by interferon-gamma and tumour necrosis factor-alpha. Eur J Cancer 1994;30A:2119–2125.PubMedCrossRefGoogle Scholar
  20. 20.
    Nadkarni S, Mauri C, Ehrenstein MR. Anti-TNF-alpha therapy induces a distinct regulatory T cell population in patients with rheumatoid arthritis via TGF-beta. J Exp Med 2007;204: 33–39.PubMedCrossRefGoogle Scholar
  21. 21.
    Valencia X, Stephens G, Goldbach-Mansky R, Wilson M, Shevach EM, Lipsky PE. TNF downmodulates the function of human CD4+CD25hi T-regulatory cells. Blood 2006;108:253–261.PubMedCrossRefGoogle Scholar
  22. 22.
    Ray SJ, Franki SN, Pierce RH, Dimitrova S, Koteliansky V, Sprague AG, Doherty PC, de Fougerolles AR, Topham DJ. The collagen binding alpha1beta1 integrin VLA-1 regulates CD8 T cell-mediated immune protection against heterologous influenza infection. Immunity 2004;20:167–179.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  • Ilan Bank
    • 1
    • 2
  • Shomron Ben-Horin
    • 3
  • Itamar Goldstein
    • 4
  • Alexander Koltakov
    • 5
  • Pnina Langevitz
    • 2
    • 6
  • Michael Ehrenfeld
    • 2
    • 7
  • Esther Rosenthal
    • 8
  • Hanan Gur
    • 2
    • 9
  1. 1.Medicine and Laboratory for ImmunoregulationChaim Sheba Medical CenterTel HashomerIsrael
  2. 2.Sackler School of MedicineTel Aviv UniversityTel AvivIsrael
  3. 3.GastroenterologyChaim Sheba Medical CenterTel HashomerIsrael
  4. 4.Sheba Cancer Research CenterChaim Sheba Medical CenterTel HashomerIsrael
  5. 5.Laboratory for ImmunoregulationChaim Sheba Medical CenterTel HashomerIsrael
  6. 6.Medicine and RheumatologyChaim Sheba Medical CenterTel HashomerIsrael
  7. 7.MedicineChaim Sheba Medical CenterTel HashomerIsrael
  8. 8.HematologyChaim Sheba Medical CenterTel HashomerIsrael
  9. 9.MedicineSouraski Medical CenterTel AvivIsrael

Personalised recommendations