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Logo of annrheumdAnnals of the Rheumatic DiseasesCurrent TOCInstructions for authors
Ann Rheum Dis. Nov 2005; 64(Suppl 4): iv77–iv80.
PMCID: PMC1766898

How does B cell depletion therapy work, and how can it be improved?

Abstract

The past few years have seen a surge of interest in B cell depletion therapy for patients with rheumatoid arthritis. This paper outlines the possible mechanism(s) by which B cell depletion therapy works. It is likely there is more than one mechanism and the relative importance of each mechanism depends on the target cell. These include CD20-induced apoptosis, complement dependent cytotoxicity, antibody dependent cell-mediated cytotoxicity, and selective targeting and depletion of B cell subsets. The implications of these mechanisms in the further improvement of B cell depletion therapy in rheumatoid arthritis and other autoimmune diseases are discussed.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Shlomchik MJ, Madaio MP, Ni D, Trounstein M, Huszar D. The role of B cells in lpr/lpr-induced autoimmunity. J Exp Med. 1994 Oct 1;180(4):1295–1306. [PMC free article] [PubMed]
  • Chan OT, Hannum LG, Haberman AM, Madaio MP, Shlomchik MJ. A novel mouse with B cells but lacking serum antibody reveals an antibody-independent role for B cells in murine lupus. J Exp Med. 1999 May 17;189(10):1639–1648. [PMC free article] [PubMed]
  • Edwards JC, Cambridge J. Is rheumatoid arthritis a failure of B cell death in synovium? Ann Rheum Dis. 1995 Sep;54(9):696–700. [PMC free article] [PubMed]
  • Edwards JC, Cambridge G, Abrahams VM. Do self-perpetuating B lymphocytes drive human autoimmune disease? Immunology. 1999 Jun;97(2):188–196. [PMC free article] [PubMed]
  • Edwards Jonathan C W, Szczepanski Leszek, Szechinski Jacek, Filipowicz-Sosnowska Anna, Emery Paul, Close David R, Stevens Randall M, Shaw Tim. Efficacy of B-cell-targeted therapy with rituximab in patients with rheumatoid arthritis. N Engl J Med. 2004 Jun 17;350(25):2572–2581. [PubMed]
  • Edwards JCW, Cambridge G. Prospects for B-cell-targeted therapy in autoimmune disease. Rheumatology (Oxford) 2005 Feb;44(2):151–156. [PubMed]
  • Cope Andrew P, Feldmann Marc. Emerging approaches for the therapy of autoimmune and chronic inflammatory disease. Curr Opin Immunol. 2004 Dec;16(6):780–786. [PubMed]
  • Cartron Guillaume, Watier Hervé, Golay Josée, Solal-Celigny Philippe. From the bench to the bedside: ways to improve rituximab efficacy. Blood. 2004 Nov 1;104(9):2635–2642. [PubMed]
  • Valentine MA, Licciardi KA. Rescue from anti-IgM-induced programmed cell death by the B cell surface proteins CD20 and CD40. Eur J Immunol. 1992 Dec;22(12):3141–3148. [PubMed]
  • Shan D, Ledbetter JA, Press OW. Signaling events involved in anti-CD20-induced apoptosis of malignant human B cells. Cancer Immunol Immunother. 2000 Mar;48(12):673–683. [PubMed]
  • Deans JP, Schieven GL, Shu GL, Valentine MA, Gilliland LA, Aruffo A, Clark EA, Ledbetter JA. Association of tyrosine and serine kinases with the B cell surface antigen CD20. Induction via CD20 of tyrosine phosphorylation and activation of phospholipase C-gamma 1 and PLC phospholipase C-gamma 2. J Immunol. 1993 Nov 1;151(9):4494–4504. [PubMed]
  • Einfeld DA, Brown JP, Valentine MA, Clark EA, Ledbetter JA. Molecular cloning of the human B cell CD20 receptor predicts a hydrophobic protein with multiple transmembrane domains. EMBO J. 1988 Mar;7(3):711–717. [PMC free article] [PubMed]
  • Clark EA, Shu GL, Lüscher B, Draves KE, Banchereau J, Ledbetter JA, Valentine MA. Activation of human B cells. Comparison of the signal transduced by IL-4 to four different competence signals. J Immunol. 1989 Dec 15;143(12):3873–3880. [PubMed]
  • Genot EM, Meier KE, Licciardi KA, Ahn NG, Uittenbogaart CH, Wietzerbin J, Clark EA, Valentine MA. Phosphorylation of CD20 in cells from a hairy cell leukemia cell line. Evidence for involvement of calcium/calmodulin-dependent protein kinase II. J Immunol. 1993 Jul 1;151(1):71–82. [PubMed]
  • Deans Julie P, Li Haidong, Polyak Maria J. CD20-mediated apoptosis: signalling through lipid rafts. Immunology. 2002 Oct;107(2):176–182. [PMC free article] [PubMed]
  • Cragg Mark S, Morgan Suzanne M, Chan H T Claude, Morgan B Paul, Filatov AV, Johnson Peter W M, French Ruth R, Glennie Martin J. Complement-mediated lysis by anti-CD20 mAb correlates with segregation into lipid rafts. Blood. 2003 Feb 1;101(3):1045–1052. [PubMed]
  • Press OW, Appelbaum F, Ledbetter JA, Martin PJ, Zarling J, Kidd P, Thomas ED. Monoclonal antibody 1F5 (anti-CD20) serotherapy of human B cell lymphomas. Blood. 1987 Feb;69(2):584–591. [PubMed]
  • Maloney DG, Grillo-López AJ, White CA, Bodkin D, Schilder RJ, Neidhart JA, Janakiraman N, Foon KA, Liles TM, Dallaire BK, et al. IDEC-C2B8 (Rituximab) anti-CD20 monoclonal antibody therapy in patients with relapsed low-grade non-Hodgkin's lymphoma. Blood. 1997 Sep 15;90(6):2188–2195. [PubMed]
  • McLaughlin P, Grillo-López AJ, Link BK, Levy R, Czuczman MS, Williams ME, Heyman MR, Bence-Bruckler I, White CA, Cabanillas F, et al. Rituximab chimeric anti-CD20 monoclonal antibody therapy for relapsed indolent lymphoma: half of patients respond to a four-dose treatment program. J Clin Oncol. 1998 Aug;16(8):2825–2833. [PubMed]
  • Byrd John C, Kitada Shinichi, Flinn Ian W, Aron Jennifer L, Pearson Michael, Lucas David, Reed John C. The mechanism of tumor cell clearance by rituximab in vivo in patients with B-cell chronic lymphocytic leukemia: evidence of caspase activation and apoptosis induction. Blood. 2002 Feb 1;99(3):1038–1043. [PubMed]
  • Farag Sherif S, Flinn Ian W, Modali Rama, Lehman Teresa A, Young Donn, Byrd John C. Fc gamma RIIIa and Fc gamma RIIa polymorphisms do not predict response to rituximab in B-cell chronic lymphocytic leukemia. Blood. 2004 Feb 15;103(4):1472–1474. [PubMed]
  • Jazirehi Ali R, Bonavida Benjamin. Cellular and molecular signal transduction pathways modulated by rituximab (rituxan, anti-CD20 mAb) in non-Hodgkin's lymphoma: implications in chemosensitization and therapeutic intervention. Oncogene. 2005 Mar 24;24(13):2121–2143. [PubMed]
  • Kuo CT, Veselits ML, Leiden JM. LKLF: A transcriptional regulator of single-positive T cell quiescence and survival. Science. 1997 Sep 26;277(5334):1986–1990. [PubMed]
  • Di Gaetano Nicola, Cittera Elena, Nota Rachele, Vecchi Annunciata, Grieco Valeria, Scanziani Eugenio, Botto Marina, Introna Martino, Golay Josée. Complement activation determines the therapeutic activity of rituximab in vivo. J Immunol. 2003 Aug 1;171(3):1581–1587. [PubMed]
  • Cragg Mark S, Glennie Martin J. Antibody specificity controls in vivo effector mechanisms of anti-CD20 reagents. Blood. 2004 Apr 1;103(7):2738–2743. [PubMed]
  • Bannerji Rajat, Kitada Shinichi, Flinn Ian W, Pearson Michael, Young Donn, Reed John C, Byrd John C. Apoptotic-regulatory and complement-protecting protein expression in chronic lymphocytic leukemia: relationship to in vivo rituximab resistance. J Clin Oncol. 2003 Apr 15;21(8):1466–1471. [PubMed]
  • Teeling Jessica L, French Ruth R, Cragg Mark S, van den Brakel Jeroen, Pluyter Marielle, Huang Haichun, Chan Claude, Parren Paul W H I, Hack C Erik, Dechant Michael, et al. Characterization of new human CD20 monoclonal antibodies with potent cytolytic activity against non-Hodgkin lymphomas. Blood. 2004 Sep 15;104(6):1793–1800. [PubMed]
  • van der Kolk LE, Grillo-López AJ, Baars JW, Hack CE, van Oers MH. Complement activation plays a key role in the side-effects of rituximab treatment. Br J Haematol. 2001 Dec;115(4):807–811. [PubMed]
  • Cartron Guillaume, Dacheux Laurent, Salles Gilles, Solal-Celigny Philippe, Bardos Pierre, Colombat Philippe, Watier Hervé Therapeutic activity of humanized anti-CD20 monoclonal antibody and polymorphism in IgG Fc receptor FcgammaRIIIa gene. Blood. 2002 Feb 1;99(3):754–758. [PubMed]
  • Weng Wen-Kai, Levy Ronald. Two immunoglobulin G fragment C receptor polymorphisms independently predict response to rituximab in patients with follicular lymphoma. J Clin Oncol. 2003 Nov 1;21(21):3940–3947. [PubMed]
  • Clynes RA, Towers TL, Presta LG, Ravetch JV. Inhibitory Fc receptors modulate in vivo cytotoxicity against tumor targets. Nat Med. 2000 Apr;6(4):443–446. [PubMed]
  • Uchida Junji, Hamaguchi Yasuhito, Oliver Julie A, Ravetch Jeffrey V, Poe Jonathan C, Haas Karen M, Tedder Thomas F. The innate mononuclear phagocyte network depletes B lymphocytes through Fc receptor-dependent mechanisms during anti-CD20 antibody immunotherapy. J Exp Med. 2004 Jun 21;199(12):1659–1669. [PMC free article] [PubMed]
  • Hernandez-Ilizaliturri Francisco J, Jupudy Venkata, Ostberg Julie, Oflazoglu Ezogelin, Huberman Amy, Repasky Elizabeth, Czuczman Myron S. Neutrophils contribute to the biological antitumor activity of rituximab in a non-Hodgkin's lymphoma severe combined immunodeficiency mouse model. Clin Cancer Res. 2003 Dec 1;9(16 Pt 1):5866–5873. [PubMed]
  • Stockmeyer B, Dechant M, van Egmond M, Tutt AL, Sundarapandiyan K, Graziano RF, Repp R, Kalden JR, Gramatzki M, Glennie MJ, et al. Triggering Fc alpha-receptor I (CD89) recruits neutrophils as effector cells for CD20-directed antibody therapy. J Immunol. 2000 Nov 15;165(10):5954–5961. [PubMed]
  • Bernasconi Nadia L, Traggiai Elisabetta, Lanzavecchia Antonio. Maintenance of serological memory by polyclonal activation of human memory B cells. Science. 2002 Dec 13;298(5601):2199–2202. [PubMed]
  • Tsokos George C. B cells, be gone--B-cell depletion in the treatment of rheumatoid arthritis. N Engl J Med. 2004 Jun 17;350(25):2546–2548. [PubMed]
  • van Nierop Kirsten, de Groot Cornelis. Human follicular dendritic cells: function, origin and development. Semin Immunol. 2002 Aug;14(4):251–257. [PubMed]
  • Clark EA, Ledbetter JA. How B and T cells talk to each other. Nature. 1994 Feb 3;367(6462):425–428. [PubMed]
  • Gong Qian, Ou Qinglin, Ye Shiming, Lee Wyne P, Cornelius Jennine, Diehl Lauri, Lin Wei Yu, Hu Zhilan, Lu Yanmei, Chen Yongmei, et al. Importance of cellular microenvironment and circulatory dynamics in B cell immunotherapy. J Immunol. 2005 Jan 15;174(2):817–826. [PubMed]
  • Hamaguchi Yasuhito, Uchida Junji, Cain Derek W, Venturi Guglielmo M, Poe Jonathan C, Haas Karen M, Tedder Thomas F. The peritoneal cavity provides a protective niche for B1 and conventional B lymphocytes during anti-CD20 immunotherapy in mice. J Immunol. 2005 Apr 1;174(7):4389–4399. [PubMed]
  • Fujimoto M, Poe JC, Hasegawa M, Tedder TF. CD19 regulates intrinsic B lymphocyte signal transduction and activation through a novel mechanism of processive amplification. Immunol Res. 2000;22(2-3):281–298. [PubMed]
  • Greten Florian R, Eckmann Lars, Greten Tim F, Park Jin Mo, Li Zhi-Wei, Egan Laurence J, Kagnoff Martin F, Karin Michael. IKKbeta links inflammation and tumorigenesis in a mouse model of colitis-associated cancer. Cell. 2004 Aug 6;118(3):285–296. [PubMed]
  • Dave Sandeep S, Wright George, Tan Bruce, Rosenwald Andreas, Gascoyne Randy D, Chan Wing C, Fisher Richard I, Braziel Rita M, Rimsza Lisa M, Grogan Thomas M, et al. Prediction of survival in follicular lymphoma based on molecular features of tumor-infiltrating immune cells. N Engl J Med. 2004 Nov 18;351(21):2159–2169. [PubMed]

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