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:

WT1 Biology

Th1-biased humoral immune responses against Wilms tumor gene WT1 product in the patients with hematopoietic malignancies

Abstract

The Wilms' tumor gene WT1 is highly expressed in leukemias and myelodysplastic syndrome (MDS), and WT1 expression levels increase along with the disease progression in chronic myeloid leukemia and MDS. We previously reported that IgM and IgG WT1 antibodies were detected with significantly higher detection rate and antibody titers in leukemias and MDS compared to those in healthy volunteers. In this study, whether IgG humoral immune responses against WT1 protein were Th1- or Th2-type were determined by measurement of four subclasses of IgG WT1 antibody, IgG1, IgG2, IgG3, and IgG4. In leukemias and MDS, Th1-type WT1 antibodies such as IgG1, IgG2, and IgG3 were significantly increased in both detection rate and antibody titers compared to those in healthy volunteers, whereas Th2-type WT1 antibody such as IgG4 did not increase. These results showed that Th1-biased humoral immune responses against WT1 protein were generated in leukemias and MDS. These results should allow us to consider that Th1-biased cellular immune responses against WT1 protein, which was essentially needed for cancer immunotherapy targeting WT1, should be elicited in patients with hematopoietic malignancies.

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

Access options

Buy this article

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

Figure 1
Figure 2
Figure 3

Similar content being viewed by others

References

  1. Call KM, Glaser T, Ito CY . Isolation and characterization of a zinc finger polypeptide gene at the human chromosome 11 Wilms' tumor locus. Cell 1990; 60: 509–520.

    Article  CAS  PubMed  Google Scholar 

  2. Gessler M, Poustka A, Cavenee W, Neve RL, Orkin SH, Bruns GA . Homozygous deletion in Wilms' tumors of a zinc-finger gene identified by chromosome jumping. Nature 1990; 343: 774–778.

    Article  CAS  PubMed  Google Scholar 

  3. Haber DA, Park S, Maheswaran S . WT1-mediated growth suppression of Wilms tumor cells expressing a WT1 splicing variant. Science 1993; 262: 2057–2059.

    Article  CAS  PubMed  Google Scholar 

  4. Algar EM, Kenney MT, Simms LA, Smith SI, Kida Y, Smith PJ . Homozygous intragenic deletion in the WT1 gene in a sporadic Wilms' tumor associated with high levels of expression of a truncated transcript. Hum Mutat 1995; 5: 221–227.

    Article  CAS  PubMed  Google Scholar 

  5. Sugiyama H . Wilm's tumor gene WT1: its oncogenic function and clinical application. Int J Hematol 2001; 73: 177–187.

    Article  CAS  PubMed  Google Scholar 

  6. Inoue K, Sugiyama H, Ogawa H, Nakagawa M, Yamagami T, Miwa H et al. WT1 as new prognostic factor and a new marker for the detection of minimal residual disease in acute leukemia. Blood 1994; 84: 3071–3079.

    CAS  PubMed  Google Scholar 

  7. Tamaki H, Ogawa H, Ohyashiki K, Tamaki H, Ogawa H, Ohyashiki K et al. The Wilms' tumor gene WT1 is a good marker for diagnosis of disease progression of myelodysplastic syndromes. Leukemia 1999; 13: 393–399.

    Article  CAS  PubMed  Google Scholar 

  8. Oji Y, Ogawa H, Tamaki H, Oka Y, Tsuboi A, Kim EH et al. Expression of the Wilm's tumor gene WT1 in solid tumors and its involvement in tumor cell growth. Jpn J Cancer Res 1999; 90: 194–204.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Miyoshi Y, Ando A, Egawa C, Taguchi T, Tamaki Y, Tamaki H et al. High expression of Wilms' tumor suppressor gene predicts poor prognosis in breast cancer patients. Clin Cancer Res 2002; 8: 1167–1171.

    CAS  PubMed  Google Scholar 

  10. Yamagami T, Sugiyama H, Inoue K, Ogawa H, Tatekawa T, Hirata M et al. Growth inhibition of human leukemic cells by WT1 (Wilms' tumor gene) antisense oligodeoxynucleotides; implications for the involvement of WT1 in leukemogenesis. Blood 1996; 87: 2878–2884.

    CAS  PubMed  Google Scholar 

  11. Inoue K, Tamaki H, Ogawa H, Oka Y, Soma T, Tatekawa T et al. Wilms' tumor gene (WT1) competes with differentiation-inducing signal in hematopoietic progenitor cells. Blood 1998; 91: 2969–2976.

    CAS  PubMed  Google Scholar 

  12. Tsuboi A, Oka Y, Ogawa H, Elisseeva OA, Li H, Kawasaki K et al. Constitutive expression of the Wilms' tumor gene WT1 inhibits the differentiation of myeloid progenitor cells but promotes their proliferation in response to granulocyte-colony stimulating factor (G-CSF). Leuk Res 1999; 23: 499–505.

    Article  CAS  PubMed  Google Scholar 

  13. Oka Y, Elisseeva OA, Tsuboi A, Ogawa H, Tamaki H, Li H et al. Human cytotoxic T-lymphocyte responses specific for peptides of the wild-type Wilms' tumor gene (WT1) product. Immunogenetics 2000; 51: 99–107.

    Article  CAS  PubMed  Google Scholar 

  14. Ohminami H, Yasukawa M, Fujita S . HLA class I-restricted lysis of leukemia cells by a CD8+ cytotoxic T-lymphocyte clone specific for WT1 peptide. Blood 2000; 95: 286–293.

    CAS  PubMed  Google Scholar 

  15. Gao L, Bellantuono I, Elsasser A, Marley SB, Gordon MY, Goldman JM et al. Selective elimination of leukemic CD34+ progenitor cells by cytotoxic T lymphocytes specific for WT1. Blood 2000; 95: 2198–2203.

    CAS  PubMed  Google Scholar 

  16. Tsuboi A, Oka Y, Udaka K, Murakami M, Masuda T, Nakano A et al. Enhanced induction of human WT1-specific cytotoxic T lymphocytes with a 9-mer WT1 peptide modified at HLA-A*2402-binding residues. Cancer Immunol Immunother 2002; 51: 614–620.

    Article  CAS  PubMed  Google Scholar 

  17. Oka Y, Udaka K, Tsuboi A, Elisseeva OA, Ogawa H, Aozasa K et al. Cancer immunotherapy targeting Wilms' tumor gene WT1 product. J Immunol 2000; 15: 1873–1880.

    Article  Google Scholar 

  18. Tsuboi A, Oka Y, Ogawa H, Elisseeva OA, Li H, Kawasaki K et al. Cytotoxic T-lymphocyte responses elicited to Wilms' tumor gene WT1 product by DNA vaccination. J Clin Immunol 2000; 20: 195–202.

    Article  CAS  PubMed  Google Scholar 

  19. Scheibenbogen C, Letsch A, Thiel E, Schmittel A, Mailaender V, Baerwolf S et al. CD8 T-cell responses to Wilms tumor gene product WT1 and proteinase 3 in patients with acute myeloid leukemia. Blood 2002; 100: 2132–2137.

    Article  CAS  PubMed  Google Scholar 

  20. Gaiger A, Carter L, Greinix H, Carter D, McNeill PD, Houghton RL et al. WT1-specific serum antibodies in patients with leukemia. Clin Cancer Res 2001; 7: 761–765.

    Google Scholar 

  21. Elisseeva OA, Oka Y, Tsuboi A, Ogata K, Wu F, Kim EH et al. Humoral immune responses against Wilms' tumor gene WT1 product in patients with hematopoietic malignancies. Blood 2002; 99: 3272–3279.

    Article  CAS  PubMed  Google Scholar 

  22. Abbas AK, Murphy KM, Sher A . Functional diversity of helper T lymphocytes. Nature 1996; 383: 787–793.

    Article  CAS  PubMed  Google Scholar 

  23. Ogawa H, Tamaki H, Ikegame K, Soma T, Kawakami M, Tsuboi A et al. The usefulness of monitoring WT1 gene transcripts for the prediction and management of relapse following allogeneic stem cell transplantation in acute type leukemia. Blood 2003; 101: 1698–1704.

    Article  CAS  PubMed  Google Scholar 

  24. Gupta RK, Siber GR . Method for quantitation of IgG subclass antibodies in mouse serum by enzyme-linked immunosorbent assay. J Immunol Methods 1995; 181: 75–81.

    Article  CAS  PubMed  Google Scholar 

  25. Gupta CK, Leszczynski J, Gupta RK, Siber GR . IgG subclass antibodies to human cytomegalovirus (CMV) in normal human plasma samples and immune globulins and their neutralizing activities. Biologicals 1996; 24: 117–124.

    Article  CAS  PubMed  Google Scholar 

  26. Hamilton RG, Adkinson Jr NF . Quantitative aspects of solid phase immunoassays. In: Kemeny DM, Challacombe SJ (eds). Theoretical and Technical Aspects of ELISA and Other Solid Phase Immunoassays, Vol. 3. New York: John Wiley & Sons, 1988, pp 57–84.

    Google Scholar 

  27. Naess LM, Rosenqvist E, Hoiby EA, Michaelsen TE . Quantitation of IgG subclass antibody responses after immunization with a group B meningococcal outer membrane vesicle vaccine, using monoclonal mouse–human chimeric antibodies as standards. J Immunol Methods 1996; 196: 41–49.

    Article  CAS  PubMed  Google Scholar 

  28. Xu H, Lohr J, Greiner M . The selection of ELISA cut-off points for testing antibody to Newcastle disease by two-graph receiver operating characteristic (TG-ROC) analysis. J Immunol Methods 1997; 208: 61–64.

    Article  CAS  PubMed  Google Scholar 

  29. Greenberg P, Cox C, LeBeau MM, Fenaux P, Morel P, Sanz G et al. International scoring system for evaluating prognosis in myelodysplastic syndromes. Blood 1997; 89: 2079–2088.

    CAS  PubMed  Google Scholar 

  30. Gnjatic S, Atanackovic D, Jager E, Matsuo M, Selvakumar A, Altorki NK et al. Survey of maturally occurring CD4+ T-cell responses against NY-ESO-1 in cancer patients: correlation with antibody responses. Proc Natl Acad Sci USA 2003; 100: 8862–8867.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Amyes E, Curnow J, Stark Z, Corlett L, Sutton I, Vincent A . Restricted IgG1 subclass of anti-Yo antibodies in paraneoplastic cerebellar degeneration. J Neuroimmunol 2001; 114: 259–264.

    Article  CAS  PubMed  Google Scholar 

  32. Hussain R, Dockrell HM, Chiang TJ . IgG subclass antibody to Mycobacterium leprae 18000 MW antigen is restricted to IgG1 and IgG3 in leprosy. Immunology 1994; 83: 495–500.

    CAS  PubMed  PubMed Central  Google Scholar 

  33. Ng WY, Thai AC, Lui KF, Yeo PP, Cheah JS . Systemic levels of cytokines and GAD-specific autoantibody isotypes in Chinese IDDM patients. Diabetes Res Clin Pract 1999; 43: 127–135.

    Article  CAS  PubMed  Google Scholar 

  34. Ngo-Giang-Huong N, Candotti D, Goubar A, Autran B, Maynart M, Sicard D, et al., for the French Asymptomatic Long-Term Study Group. HIV type 1-specific IgG2 antibodies: markers of helper T cell type 1 response and prognostic marker of long-term nonprogression. AIDS Res Hum Retroviruses 2001; 15: 1435–1446.

    Article  Google Scholar 

  35. Skyllouriotis P, Skyllouriotis-Lazarou M, Natter S, Steiner R, Spitzauer S, Kapiotis S et al. IgG subclass reactivity to human cardiac myosin in cardiomyopathy patients is indicative of a Th1-like autoimmune. Clin Exp Immunol 1999; 115: 236–247.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We thank Mariko Yamamoto and Sachie Watanabe for the preparation of the manuscript, and Machiko Mishima and Kaori Ishizaka for skillful technical assistance.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to H Sugiyama.

Additional information

Supplementary Information

Supplementary Information accompanies the paper on the Leukemia website (http://www.nature.com/leu).

Rights and permissions

Reprints and permissions

About this article

Cite this article

Wu, F., Oka, Y., Tsuboi, A. et al. Th1-biased humoral immune responses against Wilms tumor gene WT1 product in the patients with hematopoietic malignancies. Leukemia 19, 268–274 (2005). https://doi.org/10.1038/sj.leu.2403539

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.leu.2403539

Keywords

This article is cited by

Search

Quick links