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Impact of KIR/HLA genetic combinations on double umbilical cord blood transplantation outcomes. Results of a French multicentric retrospective study on behalf of the Société Francophone de Greffe de Moelle et de Thérapie Cellulaire (SFGM-TC) and the Société Francophone d’Histocompatibilité et d’Immunogénétique (SFHI)

Bone Marrow Transplantation volume 51, pages 1499–1503 (2016)Cite this article

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Full chimerism after double umbilical cord blood transplantation (dUCBT) is usually derived from only one of the two UCB units injected. Because UCB units and patients may be mismatched for HLA class I loci, T- and/or natural killer (NK) cell alloreactivities between UCB units and the patient in the graft-versus-host (GvH) direction, and between the two UCB units in the graft-versus-graft (GvG) direction should be considered.1 In contrast to T lymphocytes, there is a rapid recovery of NK cells after UCBT,2 representing the only lymphoid cell population potentially able to control leukemic relapse in the months preceding T-cell reconstitution.3 The effector functions of NK cells are tuned by inhibitory and activating receptors such as the killer cell immunoglobulin-like receptors (KIR), which are specific to allotypic determinants shared by different HLA class I molecules (referred to as KIR ligands).4 Lack of inhibitory KIR engagement can trigger alloreactive KIR+ NK cell cytotoxicity only by functionally competent NK cells.5 Although the ligands and functions of inhibitory KIRs are well documented, this is not the case for activating KIRs, except for KIR2DS16 and KIR2DS2.7 We recently demonstrated that KIR+ cord blood NK cells reconstitute the patient's hematopoietic system as soon as day 14 after dUCBT8 and that the cord blood NK cell repertoire is structured early, depending on the KIR gene content.9 Few studies have reported on the effect of KIR ligand disparities on UCBT outcome, with discordant results depending on the clinical end point or graft parameters.10, 11, 12, 13 Furthermore, none of these studies have taken into account KIR genes, especially activating ones. The impact of KIR/KIR ligand combinations in the GvG direction was only evaluated in one unicentric study,14 which reported no identifiable role of KIR/HLA genotypes on UCB dominance after dUCBT. In this multicentric study, we retrospectively studied for the first time the distribution of KIR/KIR ligand genetic combinations by comparing the characteristics of winner vs loser UCB units, and investigated the strength of KIR/KIR ligand combinations in both the GvH and GvG directions on dUCBT outcomes. Details of all the methods employed in the study are provided as Supplementary Information.

We hypothesized that the absence of significance for KIR/KIR ligand genetic combinations on UCB dominance in this large dUCBT cohort could be related to the transplant policy of each graft center and/or the heterogeneity of graft parameters. Indeed, the comparison of graft characteristics of eight centers with at least 10 dUCBT per center included in this study, highlighted the significant difference of many parameters specific to patients and/or infused UCB such as the initial diagnosis before transplant, the conditioning regimen intensity and the TBI dose, the use of anti-thymoglobulin (ATG), GvHD prophylaxis, total nucleated cell (TNC) and CD34+ cell dose infused (data not shown). In addition, the proportion of KIR/KIR ligand incompatibilities in GvH and GvG directions differed depending on each graft center. To illustrate this point, the proportion of KIR/KIR ligand incompatibilities (none, one or more than one) in the loser UCB/winner UCB direction was represented for each graft center taking into account their size (Figure 1c). Overall, given the heterogeneity of this multicentric cohort, a more homogeneous cohort of 121 dUCBT (Supplementary Table 1) was built excluding ‘atypical’ dUCBT using multivariate correspondence analysis (Figure 1d). In this case, grafts with specific patterns for some clinical characteristics, not representative of all the grafts, were removed to reduce the data heterogeneity. However, once again no significant difference between KIR/KIR ligand genetic combination frequencies, and detailed distribution of isolated and cumulative KIR/KIR ligand combinations on UCB unit dominance, was observed between patients, winner or loser UCB units in this restricted dUCBT cohort (Supplementary Figure 1).

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Acknowledgements

We would like to thank Dr Caroline Le Gall, Julie Laurent and Dr Pierre-Antoine Gourraud (Methodomics, Toulouse, France) for their support concerning statistical analysis; Dr Céline Clément (Agence de la Biomédecine, La Plaine Saint-Denis, France) for her help extracting HLA typing from French registry; and Britt House Europe (Hegenheim, France) for help in editing the manuscript. PR is a PhD student supported by an EFS P.L/Region Pays de la Loire grant. This work was supported by EFS Pays de la Loire and by grants from IRGHET 2009, Association Recherche et Transfusion 2009, Agence de la BioMédecine 2011, Etablissement Français du Sang 2011-06, Ligue contre le Cancer Grand Ouest 2013, IRGHET 2014, Etablissement Français du Sang 2014-06, Agence de la BioMédecine 2014, LabEx Transplantex 2014 and Association Leucémie Espoir Atlantique Famille.

Author contributions

PR performed KIR genotyping, interpretation of data and contributed to writing the manuscript. FM provided clinical data of dUCBT and reviewed the manuscript. NL performed KIR genotyping. OA, JFE, CP, AD, XL, MdM, AK, PL, AD, AB, LA, MF, DM, FQ, IT, AB, AP, FD, MD and AC provided DNA cord blood samples, collected HLA typing and reviewed the manuscript. DS provided KIR multiplex primers and reviewed the manuscript. EM provided HLA typing from the French Registry. NR provided clinical data from the SFGM-TC database. IYA provided clinical data from the SFGM-TC database and reviewed the manuscript. CR designed the study, reviewed the manuscript and contributed to writing the manuscript. KG designed the study, analyzed and interpreted immunogenetic data, and wrote the paper. All the authors have approved the manuscript for publication.

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Author notes

  1. C Retière and K Gagne: These are equal senior authors.

Authors and Affiliations

  1. Research Department EA4271, Université, EFS Nantes, Nantes, France,

    P Rettman, N Legrand, C Retière & K Gagne

  2. HLA Department, EFS Nantes, Nantes, France,

    F Malard, A Devys, A Cesbron & K Gagne

  3. Hematology Department, CHU Hotel Dieu Nantes, Nantes, France,

    F Malard

  4. Immunology Department, CHU Montpellier, Montpellier, France,

    O Avinens & J-F Eliaou

  5. Société Francophone d’Histocompatibilité et d’Immunogénétique (SFHI), Paris, France

    J-F Eliaou

  6. HLA Department, UMR 7268, Université Aix-Marseille, EFS Marseille, Marseille, France,

    C Picard

  7. HLA Department, EFS Besançon, Besançon, France,

    A Dormoy

  8. HLA Department, EFS Bordeaux, Bordeaux, France,

    X Lafarge

  9. HLA Department, CHU Nice, Nice, France,

    M de Matteis

  10. HLA laboratory, CHU Nancy, Nancy, France,

    A Kennel

  11. HLA Department, Inserm UMR940, AP-HP Paris Saint Louis, Paris, France,

    P Loiseau

  12. Labex Transplantex, Université Strasbourg, Strasbourg, France,

    P Loiseau, A Cesbron & K Gagne

  13. HLA Department, EFS Angers, Angers, France,

    A Devys

  14. HLA Department, AP-HP Paris Saint-Antoine, Paris, France,

    A Boudifa

  15. HLA Department, EFS Saint-Etienne, Saint-Etienne, France,

    L Absi

  16. HLA Department, CHU Toulouse, Toulouse, France,

    M Fort

  17. HLA Department, EFS Grenoble, Grenoble, France,

    D Masson

  18. HLA Department, EFS Clermont-Ferrand, Clermont-Ferrand, France,

    F Quainon

  19. Immunology Department, Pitié Salpêtrière Charles Foix, Paris, France,

    I Theodorou

  20. HLA Department, EFS Caen, Caen, France,

    A Batho

  21. HLA Department, EFS Strasbourg, Strasbourg, France,

    A Parissiadis

  22. HLA Department, EFS Créteil, Paris, France,

    F Delbos

  23. HLA Department, CHU Limoges, Limoges, France,

    M Drouet

  24. Division of Hematology and Bone Marrow Transplantation, City of Hope, National Medical Center, Duarte, CA, USA

    D Senitzer

  25. Registre France Greffe de Moelle (RFGM), Saint-Denis La Plaine, France,

    E Marry

  26. Société Francophone de Greffe de Moelle et de Thérapie Cellulaire (SFGM-TC), Paris, France

    N Raus & I Yakoub-Agha

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  1. P Rettman
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Correspondence to K Gagne.

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Rettman, P., Malard, F., Legrand, N. et al. Impact of KIR/HLA genetic combinations on double umbilical cord blood transplantation outcomes. Results of a French multicentric retrospective study on behalf of the Société Francophone de Greffe de Moelle et de Thérapie Cellulaire (SFGM-TC) and the Société Francophone d’Histocompatibilité et d’Immunogénétique (SFHI). Bone Marrow Transplant 51, 1499–1503 (2016). https://doi.org/10.1038/bmt.2016.151

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