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.

  • Letter to the Editor
  • Published:

HLA-class II disparity is necessary for effective T cell mediated Graft-versus-Leukemia effects in NOD/scid mice engrafted with human acute lymphoblastic leukemia

Leukemia volume 27, pages 985–987 (2013)Cite this article

Subjects

Relapses of hematological malignancies after human leukocyte antigen (HLA)-matched allogeneic stem cell transplantation (alloSCT) are a major cause of treatment failure.1 Although posttransplant relapses of chronic myeloid leukemia (CML) in chronic phase can be effectively treated with donor lymphocyte infusion (DLI), curative responses in patients with B-lineage acute lymphoblastic leukemia (ALL) and CML in lymphoid blastic phase (CML-BP) are limited.1 The efficacy of DLI after HLA-matched alloSCT is mediated by donor T cells targeting polymorphic antigens presented on patient-derived malignant and non-malignant cells, but not on donor-derived cells, in the context of shared HLA molecules.2 These T cells are known to reside in the naive T cell repertoire and require priming by professional antigen presenting cells (APC) for functional activation.3, 4, 5, 6 Early after alloSCT, residual patient-derived professional APC may trigger Graft-versus-Leukemia (GvL) responses against antigens shared between APC and the patient’s malignant cells. Late after alloSCT, however, when professional APC are of donor origin, the ability of malignant cells to elicit effective GvL responses after HLA-matched DLI may depend on their capacity to serve as professional APC. ALL and CML-BP cells lack a professional APC phenotype, and their in vitro modification into leukemic APC is probably necessary for efficient generation of leukemia-reactive T cells from HLA-matched donors.7, 8, 9

In conclusion, our NOD/scid mouse model shows impairment of HLA-matched DLI to mediate GvL reactivity against established ALL and CML-BP, whereas the in vivo immunogenicity of the leukemic cells was sufficiently high to generate effective T cell responses across HLA-class II barriers. The failure of HLA-matched DLI to induce anti-tumor immunity in NOD/scid mice suggests that patients with relapsed ALL and CML-BP after alloSCT, when professional APC are of donor origin, may be unlikely to respond to HLA-matched DLI. Our data emphasize the relevance of HLA-class II disparity for efficient induction of GvL immunity against poorly immunogenic ALL and CML-BP, and support the use of HLA-class II mismatched unrelated alloSCT and DLI as treatment modality to improve clinical outcome for patients with HLA-class II positive, high-risk ALL and CML-BP.

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

Relevant articles

Open Access articles citing this article.

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Figure 1
Figure 2

References

  1. Porter DL, Alyea EP, Antin JH, DeLima M, Estey E, Falkenburg JH et al. NCI First International Workshop on the Biology, Prevention, and Treatment of Relapse after Allogeneic Hematopoietic Stem Cell Transplantation: Report from the Committee on Treatment of Relapse after Allogeneic Hematopoietic Stem Cell Transplantation. Biol Blood Marrow Transplant 2010; 16: 1467–1503.

    Article  Google Scholar 

  2. Bleakley M, Riddell SR . Exploiting T cells specific for human minor histocompatibility antigens for therapy of leukemia. Immunol Cell Biol 2011; 89: 396–407.

    Article  CAS  Google Scholar 

  3. Croft M . Activation of naive, memory and effector T cells. Curr Opin Immunol 1994; 6: 431–437.

    Article  CAS  Google Scholar 

  4. Croft M, Dubey C . Accessory molecule and costimulation requirements for CD4 T cell response. Crit Rev Immunol 1997; 17: 89–118.

    Article  CAS  Google Scholar 

  5. Sharpe AH, Freeman GJ . The B7-CD28 superfamily. Nat Rev Immunol 2002; 2: 116–126.

    Article  CAS  Google Scholar 

  6. Sallusto F, Lanzavecchia A . The instructive role of dendritic cells on T-cell responses. Arthritis Res 2002; 4 (Suppl 3): S127–S132.

    Article  Google Scholar 

  7. Smit WM, Rijnbeek M, van Bergen CA, de Paus RA, Vervenne HA, van de KM et al. Generation of dendritic cells expressing bcr-abl from CD34-positive chronic myeloid leukemia precursor cells. Hum Immunol 1997; 53: 216–223.

    Article  CAS  Google Scholar 

  8. Cignetti A, Bryant E, Allione B, Vitale A, Foa R, Cheever MA . CD34(+) acute myeloid and lymphoid leukemic blasts can be induced to differentiate into dendritic cells. Blood 1999; 94: 2048–2055.

    CAS  PubMed  Google Scholar 

  9. Jedema I, Meij P, Steeneveld E, Hoogendoorn M, Nijmeijer BA, van de MM et al. Early detection and rapid isolation of leukemia-reactive donor T cells for adoptive transfer using the IFN-gamma secretion assay. Clin Cancer Res 2007; 13: 636–643.

    Article  CAS  Google Scholar 

  10. King MA, Covassin L, Brehm MA, Racki W, Pearson T, Leif J et al. Human peripheral blood leucocyte non-obese diabetic-severe combined immunodeficiency interleukin-2 receptor gamma chain gene mouse model of xenogeneic graft-versus-host-like disease and the role of host major histocompatibility complex. Clin Exp Immunol 2009; 157: 104–118.

    Article  CAS  Google Scholar 

  11. Melenhorst JJ, Scheinberg P, Williams A, Ambrozak DR, Keyvanfar K, Smith M et al. Alloreactivity across HLA barriers is mediated by both naive and antigen-experienced T cells. Biol Blood Marrow Transplant 2011; 17: 800–809.

    Article  CAS  Google Scholar 

  12. Berard M, Tough DF . Qualitative differences between naive and memory T cells. Immunology 2002; 106: 127–138.

    Article  CAS  Google Scholar 

  13. Petersdorf EW . Optimal HLA matching in hematopoietic cell transplantation. Curr Opin Immunol 2008; 20: 588–593.

    Article  CAS  Google Scholar 

  14. Rutten CE, van Luxemburg-Heijs SA, Griffioen M, Marijt EW, Jedema I, Heemskerk MH et al. HLA-DP as specific target for cellular immunotherapy in HLA class II-expressing B-cell leukemia. Leukemia 2008; 22: 1387–1394.

    Article  CAS  Google Scholar 

  15. Stevanovic S, Griffioen M, Nijmeijer BA, van Schie ML, Stumpf AN, Rutten CE et al. Human allo-reactive CD4+ T cells as strong mediators of anti-tumor immunity in NOD/scid mice engrafted with human acute lymphoblastic leukemia. Leukemia 2012; 26: 312–322.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This study was supported by grant 2008-4263 from the Dutch Cancer Society.

Author information

Authors and Affiliations

  1. Department of Hematology, Leiden University Medical Center, Leiden, The Netherlands

    S Stevanović, M L J van Schie, M Griffioen & J H Falkenburg

Authors
  1. S Stevanović
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. M L J van Schie
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. M Griffioen
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. J H Falkenburg
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to S Stevanović.

Ethics declarations

Competing interests

The authors declare no conflict of interest.

Additional information

Supplementary Information accompanies the paper on the Leukemia website

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Stevanović, S., van Schie, M., Griffioen, M. et al. HLA-class II disparity is necessary for effective T cell mediated Graft-versus-Leukemia effects in NOD/scid mice engrafted with human acute lymphoblastic leukemia. Leukemia 27, 985–987 (2013). https://doi.org/10.1038/leu.2012.270

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/leu.2012.270

This article is cited by

Search

Advanced search

Quick links