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 Article
  • Published:

Post-Transplant Events

Activating KIR genes are associated with CMV reactivation and survival after non-T-cell depleted HLA-identical sibling bone marrow transplantation for malignant disorders

Abstract

Combinations of HLA and killer immunoglobulin-like receptors (KIR) may affect outcome in T-cell depleted haematopoietic stem cell transplantation (HSCT). The KIR gene family includes inhibitory (KIR2DL and 3DL) and activating receptors (KIR2DS). Ligands are HLA-C (KIR2D) and HLA-Bw4 (KIR3DL1) for inhibitory KIR and are still unknown for activating KIR. The impact of activating KIR genotypes from donor and recipient is poorly documented in HSCT outcome. Here, HLA and KIR genotypes were determined in 131 pairs from non-T-cell depleted HLA-identical sibling HSCT. No effect of ‘missing KIR ligand’ was detected on acute graft-versus-host disease (GVHD), relapse, survival or infections even in myeloid malignancies. However, additional activating KIR genes in the donor compared to the recipient's genotype or an identity between donor and recipient activating KIR genotypes was associated with a lower transplant-related mortality (TRM) (P=0.005) and in a multivariate analysis with a better survival (P=0.02, HR=0.28; P=0.013, HR=0.29) and a lower incidence of cytomegalovirus (CMV) reactivation (P=0.009, HR=0.36). These data highlight the impact of donor-activating KIR genes on TRM, overall survival and CMV reactivation in HLA-identical sibling HSCT.

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

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

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

Figure 1
Figure 2
Figure 3
Figure 4

Similar content being viewed by others

References

  1. Parham P . MHC class I molecules and KIRs in human history, health and survival. Nat Rev Immunol 2005; 5: 201–214.

    Article  CAS  Google Scholar 

  2. Stewart CA, Laugier-Anfossi F, Vély F, Saulquin X, Riedmuller J, Tisserant A et al. Recognition of peptide-MHC class I complexes by activating killer immunoglobulin-like receptors. PNAS 2005; 102: 13224–13229.

    Article  CAS  Google Scholar 

  3. Cudkowicz G, Bennett M . Peculiar immunobiology of bone marrow allografts. II. Rejection of parental grafts by resistant F 1 hybrid mice. J Exp Med 1971; 134: 1513–1528.

    Article  CAS  Google Scholar 

  4. Ruggeri L, Capanni M, Casucci M, Volpi I, Tosti A, Perruccio K et al. Role of natural killer cell alloreactivity in HLA-mismatched hematopoietic stem cell transplantation. Blood 1999; 94: 333–339.

    CAS  PubMed  Google Scholar 

  5. 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: 2097–2100.

    Article  CAS  Google Scholar 

  6. Leung W, Iyengar R, Turner V, Lang P, Bader P, Conn P et al. Determinants of antileukemia effects of allogeneic NK cells. J Immuno 2004; 172: 644–650.

    Article  CAS  Google Scholar 

  7. 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 

  8. Beelen DW, Ottinger HD, Ferencik S, Elmaagacli AH, Peceny R, Trenschel R et al. Genotypic inhibitory killer immunoglobulin-like receptor ligand incompatibility enhances the long-term antileukemic effect of unmodified allogeneic hematopoietic stem cell transplantation in patients with myeloid leukemias. Blood 2005; 105: 2594–2600.

    Article  CAS  Google Scholar 

  9. 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 

  10. Schaffer M, Malmberg KJ, Ringden O, Ljunggren HG, Remberger M . Increased infection-related mortality in KIR-ligand-mismatched unrelated allogeneic hematopoietic stem-cell transplantation. Transplantation 2004; 78: 1081–1085.

    Article  Google Scholar 

  11. 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: 2860–2861.

    Article  Google Scholar 

  12. Hsu KC, Keever-Taylor CA, Wilton A, Pinto C, Heller G, Arkun K et al. Improved outcome in HLA-identical sibling hematopoietic stem-cell transplantation for acute myelogenous leukemia predicted by KIR and HLA genotypes. Blood 2005; 105: 4878–4884.

    Article  CAS  Google Scholar 

  13. 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 

  14. Cook M, Briggs D, Craddock C, Mahendra P, Milligan D, Fegan C et al. Donor KIR genotype has a major influence on the rate of cytomegalovirus reactivation following T-cell replete stem cell transplantation. Blood 2006; 107: 1230–1232.

    Article  CAS  Google Scholar 

  15. Rajagopalan S, Long EO . Understanding how combinations of HLA and KIR genes influence disease. J Exp Med 2005; 201: 1025–1029.

    Article  CAS  Google Scholar 

  16. Boeckh M, Gooley TA, Myerson D, Cunningham T, Schoch G, Bowden RA . Cytomegalovirus pp65 antigenemia-guided early treatment with ganciclovir versus ganciclovir at engraftment after allogeneic marrow transplantation: a randomized double-blind study. Blood 1996; 88: 4063–4071.

    CAS  PubMed  Google Scholar 

  17. Ljungman P, Aschan J, Lewensohn-Fuchs I, Carlens S, Larsson K, Lönnqvist B et al. Results of different strategies for reducing cytomegalovirus-associated mortality in allogeneic stem cell transplant recipients. Transplantation 1998; 66: 1330–1334.

    Article  CAS  Google Scholar 

  18. Glucksberg H, Storb R, Fefer A, Buckner CD, Neiman PE, Clift RA et al. Clinical manifestations of graft-versus-host diseasein human recipients of marrow from HLA-matched sibling donors. Transplantation 1974; 18: 295–304.

    Article  CAS  Google Scholar 

  19. Rocha V, Franco RF, Porcher R, Bittencourt H, Silva Jr WA, Latouche A et al. Host defense and inflammatory gene polymorphisms are associated with outcomes after HLA-identical sibling bone marrow transplantation. Blood 2002; 100: 3908–3918.

    Article  CAS  Google Scholar 

  20. Uhrberg M, Parham P, Wernet P . Definition of gene content for nine common group B haplotypes of the Caucasoid population: KIR haplotypes contain between seven and eleven KIR genes. Immunogenetics 2002; 54: 221–229.

    Article  CAS  Google Scholar 

  21. Fine JP, Gray RJ . A proportional hazards model for the subdistributionof a competiting risk. JASA 1999; 94: 496–509.

    Article  Google Scholar 

  22. Becker S, Tonn T, Füssel T, Uhrberg M, Bogdanow M, Seifried E et al. Assessment of killer cell immunoglobulinlike receptor expression and corresponding HLA class I phenotypes demonstrates heterogenous KIR expression independent of anticipated HLA class I ligands. Hum Immunol 2003; 64: 183–193.

    Article  CAS  Google Scholar 

  23. Gagne K, Brizard G, Gueglio B, Milpied N, Herry P, Bonneville F et al. Relevance of KIR gene polymorphisms in bone marrow transplantation outcome. Hum Immunol 2002; 63: 271–280.

    Article  CAS  Google Scholar 

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

    Article  Google Scholar 

  25. Yen JH, Moore BE, NakajimaT, Scholl D, Schaid DJ, Weyand CM et al. Major histocompatibility complex class I-recognizing receptors are disease risk genes in rheumatoid arthritis. J Exp Med 2001; 193: 1159–1167.

    Article  CAS  Google Scholar 

  26. Momot T, Koch S, Hunzelmann N, Krieg T, Ulbricht K, Schmidt RE et al. Association of killer cell immunoglobulin-like receptors with scleroderma. Arthritis Rheum 2004; 50: 1561–1565.

    Article  CAS  Google Scholar 

  27. Martin MP, Nelson G, Lee JH, Pellett F, Gao X, Wade J et al. Cutting edge: susceptibility to psoriatic arthritis: influence of activating killer Ig-like receptor genes in the absence of specific HLA-C alleles. J Immunol 2002; 169: 2818–2822.

    Article  CAS  Google Scholar 

  28. 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 

  29. Nikitina-Zake L, Rajalingham R, Rumba I, Sanjeevi CB . Killer cell immunoglobulin-like receptor genes in Latvian patients with type 1 diabetes mellitus and healthy controls. Ann NY Acad Sci 2004; 1037: 161–169.

    Article  CAS  Google Scholar 

  30. 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 

  31. 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 

  32. Khakoo SI, Thio CL, Martin MP, Brooks CR, Gao X, Astemborski J et al. HLA and NK cell inhibitory receptor genes in resolving hepatitis C virus infection. Science 2004; 305: 872–874.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

We thank Nathalie David, Françoise Fecamp, Monique Dourche, Catherine Ifrah, Estelle Galup, Françoise Grignon, Mauricette Touzot, Sylvie Quintin, Benoit Tixier, Fatna Mahroug and Hélène Bleux for technical assistance. This work was supported by 100% la vie, FRM (ARS 2000), Eurobank (QLRI-CT-2000-00010), Allostem FP6 (#503319) and by PRA (B01-07).

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to P Loiseau.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Chen, C., Busson, M., Rocha, V. et al. Activating KIR genes are associated with CMV reactivation and survival after non-T-cell depleted HLA-identical sibling bone marrow transplantation for malignant disorders. Bone Marrow Transplant 38, 437–444 (2006). https://doi.org/10.1038/sj.bmt.1705468

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.bmt.1705468

Keywords

This article is cited by

Search

Quick links