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Springer Seminars in Immunopathology

, Volume 27, Issue 4, pp 443–456 | Cite as

Biological therapies directed against cells in autoimmune disease

  • Paul HaslerEmail author
Original Article

Abstract

Among the cells of the immune system involved in the pathogenesis of autoimmune disease, T cells have received the most attention. The central role of these cells in several animal models of autoimmune diseases and in human disease counterparts has provided the rationale for specific therapeutic targeting of T cell subsets, especially CD4 T cells. So far, the applicability of this approach has not been clearly evident in clinical trials, which was also the case when nondepleting “coating” anti-CD4 monoclonal antibodies was used. In the past several years, experimental evidence supporting a major role of B cells in systemic autoimmune disease has grown. This includes the pathogenicity of certain autoantibodies, the potential of B cells to present antigen in the context of MHC Class II and to signal via costimulatory molecules, and to secrete proinflammatory cytokines. In some instances, engagement of the B cell receptor and other surface receptors is sufficient to stimulate B cells to produce antibodies. The depletion of B cells by targeting the surface marker CD20 has been shown to be effective in treating rheumatoid arthritis with a good side effect profile. Series of cases with other systemic autoimmune diseases indicate that this strategy may be effective in these conditions too. The clinical data add weight to the importance of B cells in the pathogenesis of autoimmune diseases.

Keywords

Rheumatoid Arthritis Rheumatoid Arthritis Patient Systemic Lupus Erythematosus Patient Cell Depletion Adjuvant Arthritis 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

References

  1. 1.
    Walport MJ (2001) Complement. Second of two parts. N Engl J Med 344:1140–1144PubMedCrossRefGoogle Scholar
  2. 2.
    Walport MJ (2001) Complement. First of two parts. N Engl J Med 344:1058–1066PubMedCrossRefGoogle Scholar
  3. 3.
    Dayer JM, Fenner H (1992) The role of cytokines and their inhibitors in arthritis. Baillieres Clin Rheumatol 6:485–516PubMedCrossRefGoogle Scholar
  4. 4.
    McMurray RW (1996) Adhesion molecules in autoimmune disease. Semin Arthritis Rheum 25:215–233PubMedCrossRefGoogle Scholar
  5. 5.
    Leipe J, Skapenko A, Lipsky PE, Schulze-Koops H (2005) Regulatory T cells in rheumatoid arthritis. Arthritis Res Ther 7:93–99PubMedCrossRefGoogle Scholar
  6. 6.
    Bennett SR, Falta MT, Bill J, Kotzin BL (2003) Antigen-specific T cells in rheumatoid arthritis. Curr Rheumatol Rep 5:255–263PubMedCrossRefGoogle Scholar
  7. 7.
    Nissler K, Pohlers D, Huckel M, Simon J, Brauer R, Kinne RW (2004) Anti-CD4 monoclonal antibody treatment in acute and early chronic antigen induced arthritis: influence on macrophage activation. Ann Rheum Dis 63:1470–1477PubMedCrossRefGoogle Scholar
  8. 8.
    Williams RO, Marinova-Mutafchieva L, Feldmann M, Maini RN (2000) Evaluation of TNF-alpha and IL-1 blockade in collagen-induced arthritis and comparison with combined anti-TNF-alpha/anti-CD4 therapy. J Immunol 165:7240–7245PubMedGoogle Scholar
  9. 9.
    Chu CQ, Londei M (1996) Induction of Th2 cytokines and control of collagen-induced arthritis by nondepleting anti-CD4 Abs. J Immunol 157:2685–2689PubMedGoogle Scholar
  10. 10.
    Pohlers D, Schmidt-Weber CB, Franch A, Kuhlmann J, Brauer R, Emmrich F, Kinne RW (2002) Differential clinical efficacy of anti-CD4 monoclonal antibodies in rat adjuvant arthritis is paralleled by differential influence on NF-kappaB binding activity and TNF-alpha secretion of T cells. Arthritis Res 4:184–189PubMedCrossRefGoogle Scholar
  11. 11.
    Pelegri C, Castell M, Serra M, Rabanal M, Rodriguez-Palmero M, Castellote C, Franch A (2001) Prevention of adjuvant arthritis by the W3/25 anti-CD4 monoclonal antibody is associated with a decrease of blood CD4(+)CD45RC(high) T cells. Clin Exp Immunol 125:470–477PubMedCrossRefGoogle Scholar
  12. 12.
    Wendling D, Wijdenes J, Racadot E, Morel-Fourrier B (1991) Therapeutic use of monoclonal anti-CD4 antibody in rheumatoid arthritis. J Rheumatol 18:325–327PubMedGoogle Scholar
  13. 13.
    Wendling D, Racadot E, Wijdenes J, Sibilia J, Flipo RM, Cantagrel A, Miossec P, Eschard JP, Macro M, Bertin P, Liote F, Debiais F, Juvin R, Le Goff P, Masson C (1998) A randomized, double blind, placebo controlled multicenter trial of murine anti-CD4 monoclonal antibody therapy in rheumatoid arthritis. J Rheumatol 25:1457–1461PubMedGoogle Scholar
  14. 14.
    Horneff G, Krause A, Emmrich F, Kalden JR, Burmester GR (1991) Elevated levels of circulating tumor necrosis factor-alpha, interferon-gamma, and interleukin-2 in systemic reactions induced by anti-CD4 therapy in patients with rheumatoid arthritis. Cytokine 3:266–267PubMedCrossRefGoogle Scholar
  15. 15.
    Winsor-Hines D, Merrill C, O’Mahony M, Rao PE, Cobbold SP, Waldmann H, Ringler DJ, Ponath PD (2004) Induction of immunological tolerance/hyporesponsiveness in baboons with a nondepleting CD4 antibody. J Immunol 173:4715–4723PubMedGoogle Scholar
  16. 16.
    Ehrenstein MR, Evans JG, Singh A, Moore S, Warnes G, Isenberg DA, Mauri C (2004) Compromised function of regulatory T cells in rheumatoid arthritis and reversal by anti-TNFalpha therapy. J Exp Med 200:277–285PubMedCrossRefGoogle Scholar
  17. 17.
    Mason U, Aldrich J, Breedveld F, Davis CB, Elliott M, Jackson M, Jorgensen C, Keystone E, Levy R, Tesser J, Totoritis M, Truneh A, Weisman M, Wiesenhutter C, Yocum D, Zhu J (2002) CD4 coating, but not CD4 depletion, is a predictor of efficacy with primatized monoclonal anti-CD4 treatment of active rheumatoid arthritis. J Rheumatol 29:220–229PubMedGoogle Scholar
  18. 18.
    Moreland LW, Haverty TP, Wacholtz MC, Knowles RW, Bucy RP, Heck LW Jr, Koopman WJ (1998) Nondepleting humanized anti-CD4 monoclonal antibody in patients with refractory rheumatoid arthritis. J Rheumatol 25:221–228PubMedGoogle Scholar
  19. 19.
    Choy EH, Pitzalis C, Cauli A, Bijl JA, Schantz A, Woody J, Kingsley GH, Panayi GS (1996) Percentage of anti-CD4 monoclonal antibody-coated lymphocytes in the rheumatoid joint is associated with clinical improvement. Implications for the development of immunotherapeutic dosing regimens. Arthritis Rheum 39:52–56PubMedCrossRefGoogle Scholar
  20. 20.
    Choy EH, Schantz A, Pitzalis C, Kingsley GH, Panayi GS (1998) The pharmacokinetics and human anti-mouse antibody response in rheumatoid arthritis patients treated with a chimeric anti-CD4 monoclonal antibody. Br J Rheumatol 37:801–802PubMedCrossRefGoogle Scholar
  21. 21.
    Choy EH, Panayi GS, Emery P, Madden S, Breedveld FC, Kraan MC, Kalden JR, Rascu A, Brown JC, Rapson N, Johnston JM (2002) Repeat-cycle study of high-dose intravenous 4162W94 anti-CD4 humanized monoclonal antibody in rheumatoid arthritis. A randomized placebo-controlled trial. Rheumatology (Oxford) 41:1142–1148CrossRefGoogle Scholar
  22. 22.
    Veale DJ, Reece RJ, Parsons W, Radjenovic A, O’Connor PJ, Orgles CS, Berry E, Ridgway JP, Mason U, Boylston AW, Gibbon W, Emery P (1999) Intra-articular primatised anti-CD4: efficacy in resistant rheumatoid knees. A study of combined arthroscopy, magnetic resonance imaging, and histology. Ann Rheum Dis 58:342–349PubMedCrossRefGoogle Scholar
  23. 23.
    Lebwohl M, Tyring SK, Hamilton TK, Toth D, Glazer S, Tawfik NH, Walicke P, Dummer W, Wang X, Garovoy MR, Pariser D (2003) A novel targeted T-cell modulator, efalizumab, for plaque psoriasis. N Engl J Med 349:2004–2013PubMedCrossRefGoogle Scholar
  24. 24.
    Ellis CN, Krueger GG (2001) Treatment of chronic plaque psoriasis by selective targeting of memory effector T lymphocytes. N Engl J Med 345:248–255PubMedCrossRefGoogle Scholar
  25. 25.
    Skov L, Kragballe K, Zachariae C, Obitz ER, Holm EA, Jemec GB, Solvsten H, Ibsen HH, Knudsen L, Jensen P, Petersen JH, Menne T, Baadsgaard O (2003) HuMax-CD4: a fully human monoclonal anti-CD4 antibody for the treatment of psoriasis vulgaris. Arch Dermatol 139:1433–1439PubMedCrossRefGoogle Scholar
  26. 26.
    Hayashi Y, Ishimaru N, Arakaki R, Tsukumo S, Fukui H, Kishihara K, Shiota H, Yasutomo K (2004) Effective treatment of a mouse model of Sjogren’s syndrome with eyedrop administration of anti-CD4 monoclonal antibody. Arthritis Rheum 50:2903–2910PubMedCrossRefGoogle Scholar
  27. 27.
    Samarkos M, Moutsopoulos HM (2005) Recent advances in the management of ocular complications of Sjogren’s syndrome. Curr Allergy Asthma Rep 5:327–332PubMedCrossRefGoogle Scholar
  28. 28.
    Liu E, Moriyama H, Paronen J, Abiru N, Miao D, Yu L, Taylor RM, Eisenbarth GS (2003) Nondepleting anti-CD4 monoclonal antibody prevents diabetes and blocks induction of insulin autoantibodies following insulin peptide B:9-23 immunization in the NOD mouse. J Autoimmun 21:213–219PubMedCrossRefGoogle Scholar
  29. 29.
    Makhlouf L, Grey ST, Dong V, Csizmadia E, Arvelo MB, Auchincloss H Jr, Ferran C, Sayegh MH (2004) Depleting anti-CD4 monoclonal antibody cures new-onset diabetes, prevents recurrent autoimmune diabetes, and delays allograft rejection in nonobese diabetic mice. Transplantation 77:990–997PubMedCrossRefGoogle Scholar
  30. 30.
    Kurts C, Sutherland RM, Davey G, Li M, Lew AM, Blanas E, Carbone FR, Miller JF, Heath WR (1999) CD8 T cell ignorance or tolerance to islet antigens depends on antigen dose. Proc Natl Acad Sci U S A 96:12703–12707PubMedCrossRefGoogle Scholar
  31. 31.
    Groen H, Klatter F, Pater J, Nieuwenhuis P, Rozing J (2003) Temporary, but essential requirement of CD8+ T cells early in the pathogenesis of diabetes in BB rats as revealed by thymectomy and CD8 depletion. Clin Dev Immunol 10:141–151PubMedCrossRefGoogle Scholar
  32. 32.
    Jiang H, Curran S, Ruiz-Vazquez E, Liang B, Winchester R, Chess L (2003) Regulatory CD8+ T cells fine-tune the myelin basic protein-reactive T cell receptor V beta repertoire during experimental autoimmune encephalomyelitis. Proc Natl Acad Sci U S A 100:8378–8383PubMedCrossRefGoogle Scholar
  33. 33.
    Field AC, Caccavelli L, Bloch MF, Bellon B (2003) Regulatory CD8+ T cells control neonatal tolerance to a Th2-mediated autoimmunity. J Immunol 170:2508–2515PubMedGoogle Scholar
  34. 34.
    Weyand CM, Goronzy JJ (2003) Ectopic germinal center formation in rheumatoid synovitis. Ann N Y Acad Sci 987:140–149PubMedCrossRefGoogle Scholar
  35. 35.
    Kang YM, Zhang X, Wagner UG, Yang H, Beckenbaugh RD, Kurtin PJ, Goronzy JJ, Weyand CM (2002) CD8 T cells are required for the formation of ectopic germinal centers in rheumatoid synovitis. J Exp Med 195:1325–1336PubMedCrossRefGoogle Scholar
  36. 36.
    Chatenoud L (2003) CD3-specific antibody-induced active tolerance: from bench to bedside. Nat Rev Immunol 3:123–132PubMedCrossRefGoogle Scholar
  37. 37.
    Kotzin BL (2005) The role of B cells in the pathogenesis of rheumatoid arthritis. J Rheumatol Suppl 73:14–18PubMedGoogle Scholar
  38. 38.
    Leadbetter EA, Rifkin IR, Hohlbaum AM, Beaudette BC, Shlomchik MJ, Marshak-Rothstein A (2002) Chromatin-IgG complexes activate B cells by dual engagement of IgM and Toll-like receptors. Nature 416:603–607PubMedCrossRefGoogle Scholar
  39. 39.
    Vossenaar ER, van Venrooij WJ (2004) Citrullinated proteins: sparks that may ignite the fire in rheumatoid arthritis. Arthritis Res Ther 6:107–111PubMedCrossRefGoogle Scholar
  40. 40.
    Vossenaar ER, Nijenhuis S, Helsen MM, van der Heijden A, Senshu T, van den Berg WB, van Venrooij WJ, Joosten LA (2003) Citrullination of synovial proteins in murine models of rheumatoid arthritis. Arthritis Rheum 48:2489–2500PubMedCrossRefGoogle Scholar
  41. 41.
    Suzuki A, Yamada R, Chang X, Tokuhiro S, Sawada T, Suzuki M, Nagasaki M, Nakayama-Hamada M, Kawaida R, Ono M, Ohtsuki M, Furukawa H, Yoshino S, Yukioka M, Tohma S, Matsubara T, Wakitani S, Teshima R, Nishioka Y, Sekine A, Iida A, Takahashi A, Tsunoda T, Nakamura Y, Yamamoto K (2003) Functional haplotypes of PADI4, encoding citrullinating enzyme peptidylarginine deiminase 4, are associated with rheumatoid arthritis. Nat Genet 34:395–402PubMedCrossRefGoogle Scholar
  42. 42.
    Lee DM, Friend DS, Gurish MF, Benoist C, Mathis D, Brenner MB (2002) Mast cells: a cellular link between autoantibodies and inflammatory arthritis. Science 297:1689–1692PubMedCrossRefGoogle Scholar
  43. 43.
    Woolley DE, Tetlow LC (2000) Mast cell activation and its relation to proinflammatory cytokine production in the rheumatoid lesion. Arthritis Res 2:65–74PubMedCrossRefGoogle Scholar
  44. 44.
    Lanzavecchia A (1990) Receptor-mediated antigen uptake and its effect on antigen presentation to class II-restricted T lymphocytes. Annu Rev Immunol 8:773–793PubMedGoogle Scholar
  45. 45.
    Tighe H, Chen PP, Tucker R, Kipps TJ, Roudier J, Jirik FR, Carson DA (1993) Function of B cells expressing a human immunoglobulin M rheumatoid factor autoantibody in transgenic mice. J Exp Med 177:109–118PubMedCrossRefGoogle Scholar
  46. 46.
    Takemura S, Braun A, Crowson C, Kurtin PJ, Cofield RH, O’Fallon WM, Goronzy JJ, Weyand CM (2001) Lymphoid neogenesis in rheumatoid synovitis. J Immunol 167:1072–1080PubMedGoogle Scholar
  47. 47.
    Takemura S, Klimiuk PA, Braun A, Goronzy JJ, Weyand CM (2001) T cell activation in rheumatoid synovium is B cell dependent. J Immunol 167:4710–4718PubMedGoogle Scholar
  48. 48.
    Roosnek E, Lanzavecchia A (1991) Efficient and selective presentation of antigen-antibody complexes by rheumatoid factor B cells. J Exp Med 173:487–489PubMedCrossRefGoogle Scholar
  49. 49.
    Rifkin IR, Leadbetter EA, Beaudette BC, Kiani C, Monestier M, Shlomchik MJ, Marshak-Rothstein A (2000) Immune complexes present in the sera of autoimmune mice activate rheumatoid factor B cells. J Immunol 165:1626–1633PubMedGoogle Scholar
  50. 50.
    Keystone E (2005) B cell targeted therapies. Arthritis Res Ther 7(Suppl 3):S13–S18PubMedCrossRefGoogle Scholar
  51. 51.
    Baker KP, Edwards BM, Main SH, Choi GH, Wager RE, Halpern WG, Lappin PB, Riccobene T, Abramian D, Sekut L, Sturm B, Poortman C, Minter RR, Dobson CL, Williams E, Carmen S, Smith R, Roschke V, Hilbert DM, Vaughan TJ, Albert VR (2003) Generation and characterization of LymphoStat-B, a human monoclonal antibody that antagonizes the bioactivities of B lymphocyte stimulator. Arthritis Rheum 48:3253–3265PubMedCrossRefGoogle Scholar
  52. 52.
    Boumpas DT, Furie R, Manzi S, Illei GG, Wallace DJ, Balow JE, Vaishnaw A (2003) A short course of BG9588 (anti-CD40 ligand antibody) improves serologic activity and decreases hematuria in patients with proliferative lupus glomerulonephritis. Arthritis Rheum 48:719–727PubMedCrossRefGoogle Scholar
  53. 53.
    Woo P, Wilkinson N, Prieur AM, Southwood T, Leone V, Livermore P, Wythe H, Thomson D, Kishimoto T (2005) Open label phase II trial of single, ascending doses of MRA in Caucasian children with severe systemic juvenile idiopathic arthritis: proof of principle of the efficacy of IL-6 receptor blockade in this type of arthritis and demonstration of prolonged clinical improvement. Arthritis Res Ther 7:R1281–R1288PubMedCrossRefGoogle Scholar
  54. 54.
    Edwards JC, Cambridge G (2001) Sustained improvement in rheumatoid arthritis following a protocol designed to deplete B lymphocytes. Rheumatology (Oxford) 40:205–211CrossRefGoogle Scholar
  55. 55.
    Leandro MJ, Edwards JC, Cambridge G (2002) Clinical outcome in 22 patients with rheumatoid arthritis treated with B lymphocyte depletion. Ann Rheum Dis 61:883–888PubMedCrossRefGoogle Scholar
  56. 56.
    De Vita S, Zaja F, Sacco S, De Candia A, Fanin R, Ferraccioli G (2002) Efficacy of selective B cell blockade in the treatment of rheumatoid arthritis: evidence for a pathogenetic role of B cells. Arthritis Rheum 46:2029–2033PubMedCrossRefGoogle Scholar
  57. 57.
    Edwards JC, Szczepanski L, Szechinski J, Filipowicz-Sosnowska A, Emery P, Close DR, Stevens RM, Shaw T (2004) Efficacy of B-cell-targeted therapy with rituximab in patients with rheumatoid arthritis. N Engl J Med 350:2572–2581PubMedCrossRefGoogle Scholar
  58. 58.
    Moore J, Ma D, Will R, Cannell P, Handel M, Milliken S (2004) A phase II study of Rituximab in rheumatoid arthritis patients with recurrent disease following haematopoietic stem cell transplantation. Bone Marrow Transplant 34:241–247PubMedCrossRefGoogle Scholar
  59. 59.
    Gottenberg JE, Guillevin L, Lambotte O, Combe B, Allanore Y, Cantagrel A, Larroche C, Soubrier M, Bouillet L, Dougados M, Fain O, Farge D, Kyndt X, Lortholary O, Masson C, Moura B, Remy P, Thomas T, Wendling D, Anaya JM, Sibilia J, Mariette X (2005) Tolerance and short term efficacy of rituximab in 43 patients with systemic autoimmune diseases. Ann Rheum Dis 64:913–920PubMedCrossRefGoogle Scholar
  60. 60.
    Bhatia A, Ell PJ, Edwards JC (2005) Anti-CD20 monoclonal antibody (rituximab) as an adjunct in the treatment of giant cell arteritis. Ann Rheum Dis 64:1099–1100PubMedCrossRefGoogle Scholar
  61. 61.
    Cervetti G, Mechelli S, Riccioni R, Galimberti S, Caracciolo F, Petrini M (2005) High efficacy of Rituximab in indolent HCV-related lymphoproliferative disorders associated with systemic autoimmune diseases. Clin Exp Rheumatol 23:877–880PubMedGoogle Scholar
  62. 62.
    Monaco S, Turri E, Zanusso G, Maistrello B (2004) Treatment of inflammatory and paraproteinemic neuropathies. Curr Drug Targets Immune Endocr Metabol Disord 4:141–148PubMedCrossRefGoogle Scholar
  63. 63.
    Zaja F, De Vita S, Mazzaro C, Sacco S, Damiani D, De Marchi G, Michelutti A, Baccarani M, Fanin R, Ferraccioli G (2003) Efficacy and safety of rituximab in type II mixed cryoglobulinemia. Blood 101:3827–3834PubMedCrossRefGoogle Scholar
  64. 64.
    Porta C, Caporali R, Montecucco C (2005) Autoimmunity in thrombotic thrombocytopenic purpura. Semin Thromb Hemost 31:633–640PubMedCrossRefGoogle Scholar
  65. 65.
    Szodoray P, Alex P, Dandapani V, Nakken B, Pesina J, Kim X, Wallis GL, Wilson PC, Jonsson R, Centola M (2004) Apoptotic effect of rituximab on peripheral blood B cells in rheumatoid arthritis. Scand J Immunol 60:209–218PubMedCrossRefGoogle Scholar
  66. 66.
    Cambridge G, Leandro MJ, Edwards JC, Ehrenstein MR, Salden M, Bodman-Smith M, Webster AD (2003) Serologic changes following B lymphocyte depletion therapy for rheumatoid arthritis. Arthritis Rheum 48:2146–2154PubMedCrossRefGoogle Scholar
  67. 67.
    Hainsworth JD (2003) Safety of rituximab in the treatment of B cell malignancies: implications for rheumatoid arthritis. Arthritis Res Ther 5(Suppl 4):S12–S16PubMedCrossRefGoogle Scholar
  68. 68.
    Cannon GW, Marble DA, Griffiths MM, Cole BC, McCall S, Schulman SF, Strand V (1995) Immunologic assessment during treatment of rheumatoid arthritis with anti-CD5 immunoconjugate. J Rheumatol 22:207–213PubMedGoogle Scholar
  69. 69.
    Olsen NJ, Brooks RH, Cush JJ, Lipsky PE, St Clair EW, Matteson EL, Gold KN, Cannon GW, Jackson CG, McCune WJ, Fox DA, Nelson B, Lorenz T, Strand V (1996) A double-blind, placebo-controlled study of anti-CD5 immunoconjugate in patients with rheumatoid arthritis. The Xoma RA Investigator Group. Arthritis Rheum 39:1102–1108PubMedCrossRefGoogle Scholar
  70. 70.
    Ruderman EM, Weinblatt ME, Thurmond LM, Pinkus GS, Gravallese EM (1995) Synovial tissue response to treatment with Campath-1H. Arthritis Rheum 38:254–258PubMedCrossRefGoogle Scholar

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© Springer-Verlag 2006

Authors and Affiliations

  1. 1.RheumaklinikKantonsspital AarauAarauSwitzerland

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