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:

Stem Cell Transplantation

A defined donor activating natural killer cell receptor genotype protects against leukemic relapse after related HLA-identical hematopoietic stem cell transplantation

Leukemia volume 19, pages 1446–1451 (2005)Cite this article

Abstract

Killer cell immunoglobulin-like receptors (KIRs) recognize different groups of Human Leukocyte Antigen (HLA) class I alleles and are expressed by natural killer (NK) cells and some T lymphocytes. NK cell cytotoxicity is triggered by failure to recognize the appropriate HLA class I ligand on target cells. Recently, it has been shown that HLA class I ligand incompatibility in the graft-versus-host (GvH) direction is associated with a better outcome in haploidentical hematopoietic stem cell transplantation (HSCT). Since KIR genotypes are very diverse in the population, we explored whether or not the donor KIR genotype could affect the graft-versus-leukemia (GvL) effect in the related HLA-identical HSCT setting. We determined the KIR and HLA genotypes of 65 HLA-identical patient–donor siblings. We found that the presence of two activating KIRs, 2DS1 and 2DS2, in the donor was significantly associated with a decreased leukemic relapse rate (P=0.03; OR=0.18; 95% CI: 0.037–0.88). Moreover, the probability of relapse at 5 years was significantly lower for patients who received a graft from a donor with the 2DS1(+)2DS2(+) genotype than for those who received a transplant from other donors (17 vs 63%, respectively; P=0.018). In conclusion, this study suggests that a joint effect of these two selected activating KIRs in the donor might confer some protection against leukemic relapse.

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

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

Similar content being viewed by others

References

  1. Miller JS . The biology of natural killer cells in cancer, infection, and pregnancy. Exp Hematol 2001; 29: 1157–1168.

    Article  CAS  Google Scholar 

  2. Biassoni R, Cantoni C, Pende D, Sivori S, Parolini S, Vitale M et al. Human natural killer cell receptors and co-receptors. Immunol Rev 2001; 181: 203–214.

    Article  CAS  Google Scholar 

  3. Farag SS, Fehniger T, Ruggeri L, Velardi A, Caligiuri MA . Natural killer cell receptors: new biology and insights into the graft-versus-leukemia effect. Blood 2002; 100: 1935–1947.

    Article  CAS  Google Scholar 

  4. Natarajan K, Dimasi N, Wang J, Mariuzza R, Margulies DH . Structure and function of natural killer cell receptors: Multiple molecular solutions to self, nonself discrimination. Annu Rev Immunol 2002; 20: 853–885.

    Article  CAS  Google Scholar 

  5. Colonna M, Brooks EG, Falco M, Ferrara GB, Strominger JL . Generation of allospecific natural killer cells by stimulation across a polymorphism of HLA-C. Science 1993; 260: 1121–1124.

    Article  CAS  Google Scholar 

  6. Moretta A, Vitale M, Bottino C, Orengo AM, Morelli L, Augugliaro R et al. P58 molecules as putative receptors for major histocompatibility complex (MHC) class I molecules in human natural killer (NK) cells: anti-P58 antibodies reconstitute lysis of MHC class I-protected cells in NK clones displaying different specificities. J Exp Med 1993; 178: 597–604.

    Article  CAS  Google Scholar 

  7. Gumperz JE, Litwin V, Phillips JH, Lanier LL, Parham P . The Bw4 public epitope of HLA-B molecules confers reactivity with NK cell clones that express NKB1, a putative HLA receptor. J Exp Med 1995; 181: 1133–1144.

    Article  CAS  Google Scholar 

  8. Döhring C, Scheidegger D, Samaridis J, Cella M, Colonna M . A human killer inhibitory receptor specific for HLA-A. J Immunol 1996; 156: 3098–3101.

    PubMed  Google Scholar 

  9. Valés-Gomez M, Reyburn HT, Erskine RA, Strominger J . Differential binding to HLA-C of p50-activating and p58-inhibitory natural killer cell receptors. Proc Natl Acad Sci USA 1998; 95: 14326–14331.

    Article  Google Scholar 

  10. Moretta A, Sivori S, Vitale M, Pende D, Morelli L, Augugliaro R et al. Existence of both inhibitory (p58) and activating (p50) receptors for HLA-C molecules in human natural killer cells. J Exp Med 1995; 182: 875–884.

    Article  CAS  Google Scholar 

  11. Biassoni R, Cantoni C, Falco M, Verdiani S, Bottino C, Vitale M et al. The human leucocyte antigen (HLA)-C-specific ‘activating’ or ‘inhibitory’ natural killer cell receptors display highly homologous extracellular domains but differ in their transmembrane and intracytoplasmic portions. J Exp Med 1996; 183: 645–650.

    Article  CAS  Google Scholar 

  12. Valés-Gomez M, Reyburn HT, Mandelboim M, Strominger J . Kinetics of interaction of HLA-ligands with natural killer cell inhibitory receptors. Immunity 1998; 9: 337–344.

    Article  Google Scholar 

  13. Smith HR, Heusel JW, Mehta IK, Kim S, Dorner BG, Naidenko OV et al. Recognition of a virus-encoded ligand by a natural killer cell activation receptor. Proc Natl Acad Sci USA 2002; 99: 8826–8831.

    Article  CAS  Google Scholar 

  14. Arase H, Mocarski ES, Campbell AE, Hill AB, Lanier LL . Direct recognition of cytomegalovirus by activating and inhibitory NK cell receptors. Science 2002; 296: 1323–1326.

    Article  CAS  Google Scholar 

  15. Katz G, Gazit R, Arnon TI, Gonen-Gross T, Tarcic G, Markel G et al. MHC class I-independent recognition of NK-activating receptor KIR2DS4. J Immunol 2004; 173: 1819–1825.

    Article  CAS  Google Scholar 

  16. Uhrberg M, Valiante NM, Shum BP . Human diversity in killer cell inhibitory receptor genes. Immunity 1997; 7: 753–763.

    Article  CAS  Google Scholar 

  17. Witt CS, Dewing C, Sayer DC, Uhrberg M, Parham P, Christiansen FT . Population frequencies and putative haplotypes of the killer cell immunoglobuline-like receptor sequences and evidence for recombination. Transplantation 1999; 68: 1784–1789.

    Article  CAS  Google Scholar 

  18. Shilling HG, Guethlein LA, Cheng NW, Gardiner CM, Rodriguez R, Parham P . Allelic polymorphism synergizes with variable gene content to individualize human KIR genotype. J Immunol 2002; 168: 2307–2315.

    Article  CAS  Google Scholar 

  19. Ljunggren HG, Karre K . In search of the missing self: MHC molecules and NK cell recognition. Immunol Today 1990; 11: 237–244.

    Article  CAS  Google Scholar 

  20. Algarra I, Cabrera T, Garrido F . The HLA crossroad in tumor immunology. Hum Immunol 2000; 61: 65–73.

    Article  CAS  Google Scholar 

  21. Elkins WL, Pickard A, Pierson GR . Deficient expression of class-I HLA in some cases of acute leukemia. Cancer Immunol Immunother 1984; 18: 91–100.

    Article  CAS  Google Scholar 

  22. Brouwer RE, van der Heiden P, Schreuder GM, Mulder A, Datema G, Anholts JD et al. Loss or downregulation of HLA class I expression at the allelic level in acute leukemia is infrequent but functionally relevant, and can be restored by interferon. Hum Immunol 2002; 63: 200–210.

    Article  CAS  Google Scholar 

  23. Demanet C, Mulder A, Deneys V, Worsham MJ, Claas FH, Ferrone S . Down-regulation of HLA-A and HLA-Bw6, but not HLA-Bw4, allospecificities in leukemic cells: an escape mechanism from CTL and NK attack? Blood 2004; 103: 3122–3130.

    Article  CAS  Google Scholar 

  24. Ruggeri L, Capanni M, Martelli MF, Velardi A . Cellular therapy: exploiting NK cell alloreactivity in transplantation. Curr Opin Immunol 2001; 8: 355–359.

    CAS  Google Scholar 

  25. Ruggeri L, Capanni M, Urbani E, Perruccio K, Shlomchik WD, Tosti A et al. Effectiveness of donor natural killer cell alloreactivity in mismatched hematopoietic transplants. Science 2002; 295: 2097–2101.

    Article  CAS  Google Scholar 

  26. Bishara A, Amar A, Brautbar C, Condiotti R, Lazarovitz V, Nagler A . The putative role of HLA-C recognition in graft versus host disease (GVHD) and graft rejection after unrelated bone marrow transplantation (BMT). Exp Hematol 1995; 23: 1667–1675.

    CAS  PubMed  Google Scholar 

  27. Giebel S, Locatelli F, Lamparelli T, Velardi A, Davies S, Frumento G et al. Survival advantage with KIR ligand incompatibility in hematopoietic stem cell transplantation from unrelated donors. Blood 2003; 102: 814–819.

    Article  CAS  Google Scholar 

  28. Verheyden S, Bernier M, Demanet C . Identification of natural killer cell receptor phenotypes associated with leukemia. Leukemia 2004; 18: 2002–2007.

    Article  CAS  Google Scholar 

  29. Maxwell LD, Williams F, Gilmore P, Meenagh A, Middleton D . Investigation of killer cell immunoglobulin-like receptor gene diversity: II. KIR2DS4. Hum Immunol 2004; 65: 613–621.

    Article  CAS  Google Scholar 

  30. Martin MP, Gao X, Lee JH, Nelson GW, Detels R, Goedert JJ et al. Epistatic interaction between KIR3DS1 and HLA-B delays the progression to AIDS. Nat Genet 2002; 31: 429–434.

    Article  CAS  Google Scholar 

  31. Nelson GW, Martin MP, Gladman D, Wade J, Trowsdale J, Carrington M . Cutting edge: heterozygote advantage in autoimmune disease: hierarchy of protection/susceptibility conferred by HLA and killer Ig-like receptor combinations in psoriatic arthritis. J Immunol 2004; 173: 4273–4276.

    Article  CAS  Google Scholar 

  32. Cook MA, Milligan DW, Fegan CD, Darbyshire PJ, Mahendra P, Craddock CF et al. The impact of donor KIR and patient HLA-C genotypes on outcome following HLA-identical sibling hematopoietic stem cell transplantation for myeloid leukemia. Blood 2004; 103: 1521–1526.

    Article  CAS  Google Scholar 

  33. Davies SM, Ruggieri L, DeFor T, Wagner JE, Weisdorf DJ, Miller JS et al. Evaluation of KIR ligand incompatibility in mismatched unrelated donor hematopoietic transplants. Blood 2002; 100: 3825–3827.

    Article  CAS  Google Scholar 

  34. Bishara A, De Santis D, Witt CC, Brautbar C, Christiansen FT, Or R et al. The beneficial role of inhibitory KIR genes of HLA class I NK epitopes in haploidentically mismatched stem cell allografts may be masked by residual donor-alloreactive T cells causing GVHD. Tissue Antigens 2004; 63: 204–211.

    Article  CAS  Google Scholar 

  35. Bornhauser M, Schwerdtfeger R, Martin H, Frank KH, Theuser C, Ehninger G . Role of KIR ligand incompatibility in hematopoietic stem cell transplantation using unrelated donors. Blood 2004; 103: 2860–2862.

    Article  Google Scholar 

  36. Gardiner CM, Guethlein LA, Shilling HG, Pando M, Carr WH, Rajalingam R et al. Different NK cell surface phenotypes defined by the DX9 antibody are due to KIR3DL1 gene polymorphism. J Immunol 2001; 166: 2992–3001.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank A Willekens and her nursing staff from the HSC Transplant Intensive Care Unit for the excellent care of the patients and clinical data collection. We also thank B Guns for editing the manuscript. We are grateful to Dr Y Van Riet and Dr S Sumbwanyambe for a critical review of the manuscript. This work was supported by a grant from the Scientific Fund W Gepts AZ-VUB.

Author information

Authors and Affiliations

  1. HLA Laboratory, Academisch ziekenhuis–Vrije Universiteit Brussel (VUB), Brussels, Belgium

    S Verheyden & C Demanet

  2. Department of Medical Oncology and Hematology, Academisch ziekenhuis–Vrije Universiteit Brussel (VUB), Brussels, Belgium

    R Schots

  3. Department of Human Biometry and Biomechanics, Vrije Universiteit Brussel (VUB), Brussels, Belgium

    W Duquet

Authors
  1. S Verheyden
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. R Schots
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. W Duquet
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. C Demanet
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to C Demanet.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Verheyden, S., Schots, R., Duquet, W. et al. A defined donor activating natural killer cell receptor genotype protects against leukemic relapse after related HLA-identical hematopoietic stem cell transplantation. Leukemia 19, 1446–1451 (2005). https://doi.org/10.1038/sj.leu.2403839

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.leu.2403839

Keywords

This article is cited by

Search

Advanced search

Quick links