title: Reconstitution of natural killer cells in HLA-matched HSCT after reduced-intensity conditioning: impact on clinical outcome.
abstract: Recent advances in the development of reduced-intensity conditioning (RIC) have allowed a broader range of patients to access allogeneic hematopoietic stem cell transplantation (HSCT). Reconstitution of an effective immune system post-transplant, including natural killer (NK) cells, is critical for both tumor control and infectious disease control or prevention. The development and functions of NK cells in such settings remain elusive. Here we analyzed NK cell development in HLA-matched HSCT from related or unrelated donors, after RIC that included antithymocyte globulin (N = 45 patients). Our data reveal that NK cells quickly recover after RIC-HSCT, irrespective of donor type. Rapidly re-emerging NK cells, however, remain immature for more than 6 months. Effector functions resemble that of immature NK cells because they poorly produce IFN-γ and TNF-α in response to target cell stimulation, despite a rapid acquisition of degranulation ability and MIP-1β production. Strikingly, rapid reconstitution of cytokine production correlates with a lower relapse incidence (P = .01) and a better survival rate (P < .0001) at 1 year post-transplant, whereas degranulation capacity was associated with less relapse (P = .05). Our study demonstrates rapid quantitative reconstitution of the NK cell compartment despite administration of potent immune suppressive drugs as part of the conditioning regimen and after transplantation. However, there is a prolonged persistence of functional defects, the correction of which positively correlates with clinical outcome.
authors.affiliation: Inserm, U1068, Centre Recherche en Cancérologie de Marseille, Institut Paoli-Calmettes, CNRS, UMR7258, Aix-Marseille University, Marseille, France.
authors.forename: Caroline
authors.initials: C
authors.lastname: Pical-Izard
authors.affiliation: Bone Marrow Transplantation Unit, Onco-Hematology Department, Institut Paoli-Calmettes, Marseille, France; Istituto Clinico Humanitas, Rozzano, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Crocchiolo
authors.affiliation: Inserm, U1068, Centre Recherche en Cancérologie de Marseille, Institut Paoli-Calmettes, CNRS, UMR7258, Aix-Marseille University, Marseille, France.
authors.forename: Samuel
authors.initials: S
authors.lastname: Granjeaud
authors.affiliation: Inserm, U1068, Centre Recherche en Cancérologie de Marseille, Institut Paoli-Calmettes, CNRS, UMR7258, Aix-Marseille University, Marseille, France.
authors.forename: Eloise
authors.initials: E
authors.lastname: Kochbati
authors.affiliation: Inserm, U1068, Centre Recherche en Cancérologie de Marseille, Institut Paoli-Calmettes, CNRS, UMR7258, Aix-Marseille University, Marseille, France.
authors.forename: Sylvaine
authors.initials: S
authors.lastname: Just-Landi
authors.affiliation: Inserm, U1068, Centre Recherche en Cancérologie de Marseille, Institut Paoli-Calmettes, CNRS, UMR7258, Aix-Marseille University, Marseille, France; Centre de Thérapie Cellulaire, Département de Biologie du Cancer, Institut Paoli-Calmettes, Marseille, France; Inserm CIC-1049, Centre d'Investigations Cliniques en Biothérapie, Marseille, France.
authors.forename: Christian
authors.initials: C
authors.lastname: Chabannon
authors.affiliation: Histocompatibility Laboratory, UMR 7268 ADÉS, Aix-Marseille Université/EFS/CNRS, Marseille, France.
authors.forename: Coralie
authors.initials: C
authors.lastname: Frassati
authors.affiliation: Histocompatibility Laboratory, UMR 7268 ADÉS, Aix-Marseille Université/EFS/CNRS, Marseille, France.
authors.forename: Christophe
authors.initials: C
authors.lastname: Picard
authors.affiliation: Inserm, U1068, Centre Recherche en Cancérologie de Marseille, Institut Paoli-Calmettes, CNRS, UMR7258, Aix-Marseille University, Marseille, France; Istituto Clinico Humanitas, Rozzano, Italy.
authors.forename: Didier
authors.initials: D
authors.lastname: Blaise
authors.affiliation: Inserm, U1068, Centre Recherche en Cancérologie de Marseille, Institut Paoli-Calmettes, CNRS, UMR7258, Aix-Marseille University, Marseille, France.
authors.forename: Daniel
authors.initials: D
authors.lastname: Olive
authors.affiliation: Inserm, U1068, Centre Recherche en Cancérologie de Marseille, Institut Paoli-Calmettes, CNRS, UMR7258, Aix-Marseille University, Marseille, France. Electronic address: cyril.fauriat@inserm.fr.
authors.forename: Cyril
authors.initials: C
authors.lastname: Fauriat
mesh_terms: D000328:Adult; D000368:Aged; D064591:Allografts; D016207:Cytokines / Q000276:immunology*; D018572:Disease-Free Survival; D005260:Female; D005500:Follow-Up Studies; D019337:Hematologic Neoplasms / Q000276:immunology / Q000401:mortality / Q000628:therapy; D018380:Hematopoietic Stem Cell Transplantation; D006650:Histocompatibility Testing; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D020127:Recovery of Function / Q000276:immunology*; D015996:Survival Rate; D019172:Transplantation Conditioning; D061349:Unrelated Donors
chemical_list: D016207:Cytokines
keywords: HLA-matched; NK cells; NK functions; Reduced-intensity conditioning; Stem cell transplantation