Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Manuscript
  • Published:

CD20 antibody (C2B8)-induced apoptosis of lymphoma cells promotes phagocytosis by dendritic cells and cross-priming of CD8+ cytotoxic T cells

Leukemia volume 15, pages 1619–1626 (2001)Cite this article

Abstract

C2B8 (Rituximab, MabThera) is a chimeric mouse/human monoclonal antibody (mAb) directed against the human B cell-restricted cell surface antigen CD20 which is used as an alternative medication in the treatment of B cell non-Hodgkin lymphomas (NHL). Treatment of CD20+ B cells with C2B8 triggers different cell damaging effects including complement-dependent lysis of tumor cells, antibody-dependent cellular cytotoxicity and induction of apoptosis. Dendritic cells (DC) have recently been shown to ingest cell debris and to present associated antigens even on MHC class I molecules, a mechanism called cross-presentation. In this study, we investigated whether C2B8 treatment of lymphoma promotes the induction of CD8+ T cell responses against lymphoma cell-associated antigens via cross-presentation. We used Daudi lymphoma cells as a model system in our studies and could demonstrate, that C2B8-treated Daudi cells undergo apoptosis, are phagocytosed by DC and induce in DC typical features of maturation; among them, the induction of CD83 expression as well as the up-regulation of prominent accessory molecules (CD40, CD86) and MHC molecules. Importantly, upon co-culture of such lymphoma cell-pulsed DC with autologous T cells, we could induce efficient cytotoxic T cell (CTL) responses against Daudi cell-associated antigens. These findings suggest that antibody treatment of tumor cells can, in addition to its direct cell damaging effects, under certain conditions, contribute to an induction of potentially protective cytotoxic T cell responses.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5
Figure 6

Similar content being viewed by others

References

  1. Reff ME, Carner K, Chambers KS, Chinn PC, Leonard JE, Rabb R, Newman RA, Hanna N, Anderson DR . Depletion of B cells in vivo by a chimeric mouse human monoclonal antibody to CD20 Blood 1994 83: 435–445

    Article  CAS  PubMed  Google Scholar 

  2. Maloney DG, Liles TM, Czerwinski DK, Waldichuk C, Rosenber J, Grillo-Lopez A, Levy R . Phase-I clinical trial using escalating single-dose infusion of chimeric anti-CD20 monoclonal antibody (IDEC-C2B8) in patients with recurrent B-cell lymphoma Blood 1994 84: 2457–2466

    Article  CAS  PubMed  Google Scholar 

  3. Tedder TF, Engel P . CD20: a regulator of cell-cycle progression of B-lymphocytes Immunol Today 1994 15: 450–454

    Article  CAS  PubMed  Google Scholar 

  4. Maloney DG, Grillo-Lopez AJ, White CA, Bodkin D, Schilder RJ, Neidhart JA, Janakiraman N, Foon KA, Liles TM, Dallaire BK, Wey I, Royston K, Davis T, Levy R . IDEC-C2B8 (Rituximab) Anti-CD20 monoclonal antibody therapy in patients with relapsed low-grade non-Hodgkin's lymphoma Blood 1997 90: 2188–2195

    Article  CAS  PubMed  Google Scholar 

  5. Maloney DG . Advances in immunotherapy of hematologic malignancies Curr Opin Haematol 1998 5: 237–243

    Article  CAS  Google Scholar 

  6. McLaughlin P, Grillo-Lopez AJ, Link BK, Levy R, Czuczman MS, Williams ME, Heyman MR, Bence-Bruckler I, White, CA, Cabanillas F, Jain, V, Ho AD, Lister J, Wey K, Shen D, Dallaire BK . 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 16: 2825–2833

    Article  CAS  PubMed  Google Scholar 

  7. Coiffier B, Haioun C, Ketterer N, Engert A, Tilly H, Ma D, Johnson P, Lister A, Feurig-Buske M, Radford JA, Capdeville R, Diel V, Reyes F . Rituximab (anti-CD20 monoclonal antibody) for the treatment of patients with relapsing or refractory agressive lymphoma: a multicenter phase II study Blood 1998 92: 1927–1932

    CAS  PubMed  Google Scholar 

  8. Hainsworth JD, Burris III HH, Morrissey LH, Litchy S, Scullin Jr DC, Bearden JD, Richards P, Greco, FA . Rituximab monoclonal antibody as initial systemic therapy for patients with low-grade non-Hodgkin lymphoma Blood 2000 95: 3052–3056

    Article  CAS  PubMed  Google Scholar 

  9. Gazzano-Santoro H, Ralph P, Ryskamp TC, Chen BA, Mukku VR . A non-radioactive complement-dependent cytotoxicity assay for anti-CD20 monoclonal antibody J Immunol Meth 1997 202: 163–171

    Article  CAS  Google Scholar 

  10. Anderson D, Grillo-Lopez A, Varns C, Chambers K, Hanna N . Targeted anti-cancer therapy using Rituximab, a chimeric anti CD20 antibody (IDEC-C2B8) in the treatment of non-Hodgkin's B-cell lymphoma Biochem Soc Trans 1997 25: 705–708

    Article  CAS  PubMed  Google Scholar 

  11. Golay J, Zaffaroni L, Vaccari T, Lazzari G-M, Borleri S, Bernasconi S, Tedesco F, Rambaldi A, Introna, M . Biologic response of B lymphoma cells to anti-CD20 monoclonal antibody rituximab in vitro: CD55 and CD59 regulate complement-mediated cell lysis Blood 2000 95: 3900–3908

    Article  CAS  PubMed  Google Scholar 

  12. Harjunpaa A, Junnikkala S, Meri S . Rituximab (anti CD20) therapy of B-cell lymphomas: direct complement killing is superior to cellular effector mechanisms Scand J Immunol 2000 51: 634–641

    Article  CAS  PubMed  Google Scholar 

  13. Shan D, Ledbetter JA, Press OW . Apoptosis of malignant human B-cells by ligation of CD20 with monoclonal antibodies Blood 1998 91: 1644–1652

    Article  CAS  PubMed  Google Scholar 

  14. Cragg MS, French RR, Glennie MJ . Signaling antibodies in cancer therapy Curr Opin Immunol 1999 11: 541–547

    Article  CAS  PubMed  Google Scholar 

  15. Shan D, Ledbetter JA, Press OW . Signaling events involved in anti-CD20-induced apoptosis of malignant human B-cells Cancer Immunol Immunother 2000 48: 673–683

    Article  CAS  PubMed  Google Scholar 

  16. Glennie MJ, Johnson PWM . Clinical trials of antibody therapy Immunol Today 2000 21: 403–410

    Article  CAS  PubMed  Google Scholar 

  17. Daniel PT . Dissecting the pathways to death Leukemia 2000 14: 2035–2044

    Article  CAS  PubMed  Google Scholar 

  18. Johnson DE . Programmed cell death regulation: basic mechanisms and therapeutic opportunities Leukemia 2000 14: 1340–1344

    Article  CAS  PubMed  Google Scholar 

  19. Fadeel B, Orrenius S, Zhivotovsky B . The most unkindest cut of all: on the multiple roles of mammalian caspases Leukemia 2000 14: 1514–1525

    Article  CAS  PubMed  Google Scholar 

  20. Fadok VA, Bratton DL, Rose DM, Ezekewitz RAB, Henson PM . A receptor for phosphatidylserine-specific clearance of apoptotic cells Nature 2000 405: 85–90

    Article  CAS  PubMed  Google Scholar 

  21. Huang AYC, Golumbek P, Ahmadzadeh M, Jaffee E, Pardoll D, Levitsky H . Role of bone marrow-derived cells in presenting MHC class-I restricted tumor antigens Science 1994 264: 961–965

    Article  CAS  PubMed  Google Scholar 

  22. Rubartelli A, Poggi A, Zocchi MR . The selective engulfment of apoptotic bodies by dendritic cells is mediated by the αvβ3 integrin and requires intracellular and extracellular calcium Eur J Immunol 1997 27: 1893–1900

    Article  CAS  PubMed  Google Scholar 

  23. Albert ML, Sauter B, Bhardwaj N . Dendritic cells acquire antigen from apoptotic cells and induce class-I restricted CTLs Nature 1998 392: 86–89

    CAS  PubMed  Google Scholar 

  24. Albert ML, Pearce SFA, Francisco LM, Sauter B, Roy P, Silverstein RL, Bhardwaj N . Immature dendritic cells phagocytose apoptotic cells via αvβ5 and CD36, and cross-present antigens to cytotoxic T lymphocytes J Exp Med 1998 188: 1359–1368

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Albert ML, Darnell JC, Bender A, Francisco LM, Bhardwaj N, Darnell RB . Tumor-specific killer cells in paraneoplastic cerebellar degeneration Nat Med 1998 4: 1321–1324

    Article  CAS  PubMed  Google Scholar 

  26. Inaba K, Turley S, Yamaide F, Iyoda K, Mahnke K, Inaba M, Pack M, Subklewe M, Sauter B, Sheff D, Albert ML, Bharwaj N, Mellman I, Steinman RM . Efficient presentation of phagocytosed cellular fragments on the major histocompatibility complex class II products of dendritic cells J Exp Med 1998 188: 2163–2173

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Kurts C, Miller JFAP, Subramaniam RM, Carbone FR, Heath WR . Major histocompatibility complex class-I restricted cross-presentation is biased towards high dose antigens and those released during cellular destruction J Exp Med 1998 188: 409–414

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Tarte K, Fiol G, Rossi JF, Klein B . Extensive characterization of dendritic cells generated in serum-free conditions: regulation of soluble antigen uptake, apoptotic tumor cell phagocytosis, chemotaxis and T cell activation during maturation in vitro Leukemia 2000 14: 2182–2192

    Article  CAS  PubMed  Google Scholar 

  29. Gallucci S, Lolkema M, Matzinger P . Natural adjuvants: endogenous activators of dendritic cells Nature Med 1999 5: 1249–1255

    Article  CAS  PubMed  Google Scholar 

  30. Sauter B, Albert ML, Francisco LM, Larrson M, Somersan S, Bhardwaj N . Consequences of cell death: exposure to necrotic tumor cells, but not primary tissue cells or apoptotic cells induces the maturation of immunostimulatory dendritic cells J Exp Med 2000 191: 423–433

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Nestle FO, Alijagic S, Gilet M, Sun Y, Grabbe S, Dummer R, Burg G, Schadendorf D . Vaccination of melanoma patients with peptide-or tumor lysate pulsed dendritic cells Nature Med 1998 4: 328–332

    Article  CAS  PubMed  Google Scholar 

  32. Albert ML, Bhardwaj N . Resurrecting the dead: DCs cross-present antigen derived from apoptotic cells on MHC-I Immunologist 1998 6: 194–198

    CAS  Google Scholar 

  33. Tarte K, Klein B . Dendritic cell based vaccine: a promising approach for cancer immunotherapy Leukemia 1999 13: 653–663

    Article  CAS  PubMed  Google Scholar 

  34. Restifo NP . Building better vaccines: how apoptotic cell death can induce inflammation and activate innate and adaptive immunity Curr Opin Immunol 2000 12: 597–603

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Yrlid U, Wick MJ . Salmonella-induced apoptosis of infected macrophages results in presentation of a bacteria-encoded antigen after uptake by bystander dendritic cells J Exp Med 2000 191: 613–621

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Steinman RM, Turley S, Mellman I, Inaba K . The induction of tolerance by dendritic cells that have captured apoptotic cells J Exp Med 2000 191: 411–416

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Seong RH, Clayberger CA, Krensky AM, Parnes JR . Rescue of Daudi cell HLA expression by transfection of the mouse β2-microglobulin gene J Exp Med 1988 167: 288–299

    Article  CAS  PubMed  Google Scholar 

  38. Browning MJ, Madrigal JA, Krausa P, Kowalski H, Allsop CE, Little AM, Turner S, Adams EJ, Arnett KL, Bodmer WF, Parham P . The HLA-A,B,C genotype of the class I negative cell line Daudi reveals novel HLA-A and -B alleles Tissue Antigens 1995 45: 177–187

    Article  CAS  PubMed  Google Scholar 

  39. Lecoeur H, Ledru E, Prevost M, Gougeon M . Strategies for phenotyping apoptotic peripheral human lymphocytes comparing ISNT, annexin-V and 7-AAD cytofluorometric staining methods J Immunol Methods 1997 209: 111–123

    Article  CAS  PubMed  Google Scholar 

  40. Katschinski DM, Robins H, Schad M, Frede S, Fandrey J . Role of tumor necrosis factor alpha in hyperthermia-induced apoptosis of human leukemia cells Cancer Res 1999 59: 3404–3410

    CAS  PubMed  Google Scholar 

  41. Pickl WF, Majdic O, Kohl P, Stöckl J, Riedl E, Scheinecker C, Bello-Fernandez C, Knapp W . Molecular and functional characteristics of dendritic cells generated from highly purified CD14+ peripheral blood monocytes J Immunol 1996 157: 3850–3859

    CAS  PubMed  Google Scholar 

  42. Sallusto F, Lanzavecchia A . Efficient presentation of soluble antigen by cultured human dendritic cells is maintained by GM/CSF plus IL4 and downregulated by TNF alpha J Exp Med 1994 179: 1109–1118

    Article  CAS  PubMed  Google Scholar 

  43. Hudson PJ . Recombinant antibody constructs in cancer therapy Curr Opin Immunol 1999 11: 548–557

    Article  CAS  PubMed  Google Scholar 

  44. Milstein C, Waldmann H . Optimism after much pessimism: what next? Curr Opin Immunol 1999 5: 589–591

    Article  Google Scholar 

  45. Miller RA, Maloney DG, Warnke R, Levy R . Treatment of B-cell lymphoma with monoclonal anti-idiotype antibody N Engl J Med 1982 306: 517–520

    Article  CAS  PubMed  Google Scholar 

  46. Davis TA, Maloney DG, Czerwinski DK, Liles TM, Levy R . Anti-idiotype antibodies can induce long-term complete remissions in non Hodgkin's lymphoma without eradicating the malignant clone Blood 1998 92: 1184–1190

    Article  CAS  PubMed  Google Scholar 

  47. Nelson EL Li X, Hsu FJ, Kwak LW, Levy R, Clayberger C, Krensky AM . Tumor-specific, cytotoxic T-lymphocyte responses after idiotype vaccination for B-cell, non-Hodgkin's lymphoma Blood 1996 15: 580–589

    Article  Google Scholar 

  48. Woiciechovsky A, Regn S, Kolb HJ, Roskrow M . Leukemic dendritic cells generated in the presence of FLT3 ligand have the capacity to stimulate an autologous leukemia-specific cytotoxic T cell response from patients with acute myeloid leukemia Leukemia 2001 15: 246–255

    Article  CAS  Google Scholar 

  49. Berinstein NL, Grillo-Lopez AJ, White CA, Bence-Bruckler I, Maloney D, Czuczman M, Green D, Rosenberg J, McLaughlin P, Shen D . Association of serum Rituximab (IDEC-C2B8) concentration and anti-tumor response in the treatment of recurrent low-grade or follicular non-Hodgkin's lymphoma Ann Oncol 1998 9: 995–1001

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by the Interdisciplinary Cooperation Programme (ICP) of the Austrian Ministry for Education, Science and Culture.

Author information

Authors and Affiliations

  1. Division of Hematology and Hemostaseology, Institute of Immunology, University of Vienna Medical School, Vienna, Austria

    N Selenko, O Majdic, S Draxler, W Knapp & J Stöckl

  2. Department of Internal Medicine-I, Division of Hematology and Hemostaseology, University of Vienna Medical School, Vienna, Austria

    A Berer & U Jäger

Authors
  1. N Selenko
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. O Majdic
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. S Draxler
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. A Berer
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. U Jäger
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. W Knapp
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. J Stöckl
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Selenko, N., Majdic, O., Draxler, S. et al. CD20 antibody (C2B8)-induced apoptosis of lymphoma cells promotes phagocytosis by dendritic cells and cross-priming of CD8+ cytotoxic T cells. Leukemia 15, 1619–1626 (2001). https://doi.org/10.1038/sj.leu.2402226

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.leu.2402226

Keywords

This article is cited by

Search

Advanced search

Quick links