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Impact of Graft-Versus-Graft Natural Killer Cell Alloreactivity on Single Unit Dominance After Double Umbilical Cord Blood Transplantation

Rettman, Pauline PhD1; Willem, Catherine1; Volteau, Christelle PhD2; Legrand, Nolwenn1; Chevallier, Patrice MD, PhD3; Lodé, Laurence MD, PhD4; Esbelin, Julie MD, PhD5; Cesbron, Anne MD, PhD6,7; Bonneville, Marc PhD8; Moreau, Philippe MD, PhD3; Senitzer, David MD, PhD9; Retière, Christelle PhD1; Gagne, Katia PhD1,6,7

doi: 10.1097/TP.0000000000001545
Original Clinical Science-General

Background: Natural killer (NK) cell alloreactivity is favored after double umbilical cord blood transplantation (dUCBT) in which cord blood (UCB) units and patients are often HLA class I mismatched. Generally, only 1 UCB unit persists after dUCBT. We hypothesize, that NK cell alloreactivity mediated by killer cell immunoglobulin-like receptor (KIR)-HLA interactions may explain the dominance of 1UCB unit over the other after dUCBT.

Methods: We investigated the impact of KIR+ NK cell alloreactivities on the dominance of 1 full UCB unit in 50 dUCBT. We analyzed the effects of the KIR/HLA genetic incompatibilities and studied cord blood cells at both the phenotypic and functional levels.

Results: The genetic combination of KIR3DL1+ loser UCB unit/Bw4 winner UCB unit determined both the dominance of 1 UCB unit (hazards ratio, 2.88 [1.32-6.27], P = 0.0077) and correlated with an increased incidence of relapse (hazards ratio, 4.91 [1.39-17.3], P = 0.0134). It is interesting to note that cord blood cells exhibited extremely low HLA class I expression. Moreover, resting cord blood KIR3DL1+ NK cells exhibited a basal alloreactivity against Bw4 target cells that increased upon activation, thus triggering death by apoptosis.

Conclusions: Our unicentric study suggests, for the first time, the significant impact of KIR+ NK cell alloreactivity in the determination of which UCB unit will dominate in dUCBT.

In this study, the authors try to understand why, in case of double umbilical cord blood transplantation, only one cord blood unit persists. In 50 patients that received a double unit cord blood transplantation, they suggest that KIR+ NK cell alloreactivity is mainly responsible for the loss of one unit.

1 Etablissement Français du Sang, Université de Nantes, Immunovirologie et Polymorphisme Génétique, Nantes, France.

2 Plateforme de Biométrie, Direction de la Recherche, CHU Nantes, France.

3 Service d'Hématologie Clinique, CHU Hotel Dieu, Nantes, France.

4 Laboratoire d'Hématologie Biologique, CHU Hotel Dieu, Nantes, France.

5 Hôpital Mère-Enfant, CHU Hotel Dieu, Nantes, France.

6 Laboratoire d'Histocompatibilité et d’Immunogénétique, EFS Nantes, France.

7 LabEx Transplantex, Université de Strasbourg, France.

8 Inserm UMR 892, Nantes, France.

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

Received 15 June 2016. Revision received 23 September 2016.

Accepted 27 September 2016.

C.R. and K.G. are equal senior authors.

This work was supported by EFS Pays de la Loire and by grants from International Research Group on unrelated HEmatopoietic stem cell Transplantation (IRGHET 2009, IRGHET 2014), Association Recherche et Transfusion 2009 (ART 2009), Agence de la BioMédecine (ABM 2011, ABM 2014), Etablissement Français du Sang (EFS 2011-06, EFS 2014-06), Ligue contre le Cancer Grand Ouest 2013, LabEx Transplantex 2014, Association Leucémie Espoir Atlantique Famille (LEAF) and Nantes Atlantique Greffe de Moëlle Osseuse (NAGMO). PR is a PhD student supported by a EFS PL/Region Pays de la Loire grant.

The authors declare no conflicts of interest.

L.L. current address, Laboratoire d’Hématologie Biologique CHRU Saint-Eloi Montpellier, France.

P.R. performed KIR genotyping, phenotype and functional studies, interpretation of data and contributed to writing the article. C.W. performed phenotype and functional studies. C.V. performed statistical analysis. N.L. performed KIR genotyping P.C. provided clinical data of dUCBT and commented on the article. L.L. collected and interpreted hematopoietic chimerism data. J.E. provided cord blood samples. A.C. collected HLA typing and commented on the article. M.B. provided advices on the study setting and edited the article. P.M. commented on the article. D.S. provided KIR multiplex primers and commented on the article. C.R. designed the study, analyzed and interpreted cellular data, commented on the manuscript and contributed to writing the article. K.G. designed the study, analyzed and interpreted immunogenetic data and wrote the article.

All the authors have approved the article for publication.

Correspondence: Katia Gagne, PhD, EFS Pays de la Loire, Université de Nantes, laboratoire EA4271, Immunovirologie et Polymorphisme Génétique, 34 Boulevard Jean Monnet, 44011 Nantes, France. (katia.gagne@efs.sante.fr); Christelle Retiere, EFS Pays de la Loire, Université de Nantes, laboratoire EA4271, Immunovirologie et Polymorphisme Génétique, 34 Boulevard Jean Monnet, 44011 Nantes, France. (christelle.retiere@efs.sante.fr).

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