title: Favorable impact of natural killer cell reconstitution on chronic graft-versus-host disease and cytomegalovirus reactivation after allogeneic hematopoietic stem cell transplantation.
abstract: Natural killer cells are the first lymphocyte subset to reconstitute, and play a major role in early immunity after allogeneic hematopoietic stem cell transplantation. Cells expressing the activating receptor NKG2C seem crucial in the resolution of cytomegalovirus episodes, even in the absence of T cells. We prospectively investigated natural killer-cell reconstitution in a cohort of 439 adult recipients who underwent non-T-cell-depleted allogeneic hematopoietic stem cell transplantation between 2005 and 2012. Freshly collected blood samples were analyzed 3, 6, 12 and 24 months after transplantation. Data were studied with respect to conditioning regimen, source of stem cells, underlying disease, occurrence of graft-versus-host disease, and profiles of cytomegalovirus reactivation. In multivariate analysis we found that the absolute numbers of CD56(bright) natural killer cells at month 3 were significantly higher after myeloablative conditioning than after reduced intensity conditioning. Acute graft-versus-host disease impaired reconstitution of total and CD56(dim) natural killer cells at month 3. In contrast, high natural killer cell count at month 3 was associated with a lower incidence of chronic graft-versus-host disease, independently of a previous episode of acute graft-versus-host disease and stem cell source. NKG2C(+)CD56(dim) and total natural killer cell counts at month 3 were lower in patients with reactivation of cytomegalovirus between month 0 and month 3, but expanded greatly afterwards. These cells were also less numerous in patients who experienced later cytomegalovirus reactivation between month 3 and month 6. Our results advocate a direct role of NKG2C-expressing natural killer cells in the early control of cytomegalovirus reactivation after allogeneic hematopoietic stem cell transplantation.
authors.affiliation: Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Saint-Louis, Laboratoire d'Immunologie et Histocompatibilité, Paris Université Paris Diderot, Sorbonne Paris Cité, Institut Universitaire d'Hématologie Paris; INSERM UMRS-1160, Paris;
authors.forename: Vissal David
authors.initials: VD
authors.lastname: Kheav
authors.affiliation: Université Paris Diderot, Sorbonne Paris Cité, Institut Universitaire d'Hématologie Paris; INSERM UMRS-1160, Paris;
authors.forename: Marc
authors.initials: M
authors.lastname: Busson
authors.affiliation: Université Paris Diderot, Sorbonne Paris Cité, Institut Universitaire d'Hématologie Paris; AP-HP, Hôpital Saint-Louis, Laboratoire de Microbiologie, Paris, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Scieux
authors.affiliation: Université Paris Diderot, Sorbonne Paris Cité, Institut Universitaire d'Hématologie Paris; AP-HP, Hôpital Saint-Louis, Service d'Hématologie-Greffe de Moelle, Paris;
authors.forename: Régis
authors.initials: R
authors.lastname: Peffault de Latour
authors.affiliation: Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Saint-Louis, Laboratoire d'Immunologie et Histocompatibilité, Paris.
authors.forename: Guitta
authors.initials: G
authors.lastname: Maki
authors.affiliation: Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Saint-Louis, Laboratoire d'Immunologie et Histocompatibilité, Paris Université Paris Diderot, Sorbonne Paris Cité, Institut Universitaire d'Hématologie Paris; INSERM UMRS-1160, Paris;
authors.forename: Philippe
authors.initials: P
authors.lastname: Haas
authors.affiliation: Université Paris Diderot, Sorbonne Paris Cité, Institut Universitaire d'Hématologie Paris; AP-HP, Hôpital Saint-Louis, Laboratoire de Microbiologie, Paris, France.
authors.forename: Marie-Christine
authors.initials: MC
authors.lastname: Mazeron
authors.affiliation: Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Saint-Louis, Laboratoire d'Immunologie et Histocompatibilité, Paris.
authors.forename: Maryvonnick
authors.initials: M
authors.lastname: Carmagnat
authors.affiliation: Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Saint-Louis, Laboratoire d'Immunologie et Histocompatibilité, Paris.
authors.forename: Emeline
authors.initials: E
authors.lastname: Masson
authors.affiliation: AP-HP, Hôpital Saint-Louis, Service d'Hématologie-Greffe de Moelle, Paris;
authors.forename: Aliénor
authors.initials: A
authors.lastname: Xhaard
authors.affiliation: AP-HP, Hôpital Saint-Louis, Service d'Hématologie-Greffe de Moelle, Paris;
authors.forename: Marie
authors.initials: M
authors.lastname: Robin
authors.affiliation: AP-HP, Hôpital Saint-Louis, Service d'Hématologie-Greffe de Moelle, Paris;
authors.forename: Patricia
authors.initials: P
authors.lastname: Ribaud
authors.affiliation: Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Saint-Louis, Laboratoire d'Immunologie et Histocompatibilité, Paris Université Paris Diderot, Sorbonne Paris Cité, Institut Universitaire d'Hématologie Paris; INSERM UMRS-1160, Paris;
authors.forename: Nicolas
authors.initials: N
authors.lastname: Dulphy
authors.affiliation: Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Saint-Louis, Laboratoire d'Immunologie et Histocompatibilité, Paris INSERM UMRS-1160, Paris;
authors.forename: Pascale
authors.initials: P
authors.lastname: Loiseau
authors.affiliation: Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Saint-Louis, Laboratoire d'Immunologie et Histocompatibilité, Paris Université Paris Diderot, Sorbonne Paris Cité, Institut Universitaire d'Hématologie Paris;
authors.forename: Dominique
authors.initials: D
authors.lastname: Charron
authors.affiliation: Université Paris Diderot, Sorbonne Paris Cité, Institut Universitaire d'Hématologie Paris; INSERM UMRS-1160, Paris; AP-HP, Hôpital Saint-Louis, Service d'Hématologie-Greffe de Moelle, Paris;
authors.forename: Gérard
authors.initials: G
authors.lastname: Socié
authors.affiliation: Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Saint-Louis, Laboratoire d'Immunologie et Histocompatibilité, Paris Université Paris Diderot, Sorbonne Paris Cité, Institut Universitaire d'Hématologie Paris; INSERM UMRS-1160, Paris; helene.moins@univ-paris-diderot.fr antoine.toubert@univ-paris-diderot.fr.
authors.forename: Antoine
authors.initials: A
authors.lastname: Toubert
authors.affiliation: Assistance Publique-Hôpitaux de Paris (AP-HP), Hôpital Saint-Louis, Laboratoire d'Immunologie et Histocompatibilité, Paris Université Paris Diderot, Sorbonne Paris Cité, Institut Universitaire d'Hématologie Paris; INSERM UMRS-1160, Paris; helene.moins@univ-paris-diderot.fr antoine.toubert@univ-paris-diderot.fr.
authors.forename: Hélène
authors.initials: H
authors.lastname: Moins-Teisserenc
mesh_terms: D000293:Adolescent; D000328:Adult; D002908:Chronic Disease; D003587:Cytomegalovirus / Q000276:immunology*; D003586:Cytomegalovirus Infections / Q000276:immunology* / Q000473:pathology / Q000821:virology; D005260:Female; D005434:Flow Cytometry; D005500:Follow-Up Studies; D006086:Graft vs Host Disease / Q000209:etiology / Q000517:prevention & control*; D019337:Hematologic Neoplasms / Q000150:complications* / Q000401:mortality / Q000628:therapy; D018380:Hematopoietic Stem Cell Transplantation / Q000009:adverse effects*; D006801:Humans; D007694:Killer Cells, Natural / Q000276:immunology*; D016131:Lymphocyte Subsets / Q000276:immunology; D008297:Male; D009367:Neoplasm Staging; D011379:Prognosis; D011446:Prospective Studies; D015996:Survival Rate; D019172:Transplantation Conditioning; D014184:Transplantation, Homologous; D014775:Virus Activation / Q000276:immunology; D055815:Young Adult
references.citation: Immunology. 2009 Apr;126(4):449-57
references.pmid: 19278418
references.citation: J Immunol. 2008 Aug 1;181(3):2227-37
references.pmid: 18641363
references.citation: Bone Marrow Transplant. 2010 Mar;45(3):543-9
references.pmid: 19617905
references.citation: J Allergy Clin Immunol. 2013 Sep;132(3):536-544
references.pmid: 23906377
references.citation: Microbes Infect. 2002 Dec;4(15):1545-58
references.pmid: 12505527
references.citation: Bone Marrow Transplant. 2001 Jul;28(2):121-9
references.pmid: 11509929
references.citation: Blood. 2001 Dec 1;98(12):3186-91
references.pmid: 11719353
references.citation: Br J Haematol. 2007 Jul;138(1):101-9
references.pmid: 17555453
references.citation: Blood. 2012 Mar 15;119(11):2665-74
references.pmid: 22180440
references.citation: N Engl J Med. 2012 Oct 18;367(16):1487-96
references.pmid: 23075175
references.citation: J Exp Med. 2011 Jan 17;208(1):13-21
references.pmid: 21173105
references.citation: Eur J Immunol. 2013 May;43(5):1133-41
references.pmid: 23552990
references.citation: Blood. 2006 May 1;107(9):3624-31
references.pmid: 16384928
references.citation: Bone Marrow Transplant. 2009 Jun;43(11):853-61
references.pmid: 19104497
references.citation: Blood. 2002 Aug 1;100(3):761-7
references.pmid: 12130483
references.citation: Semin Immunopathol. 2008 Dec;30(4):489-503
references.pmid: 19002464
references.citation: Eur J Immunol. 2012 Feb;42(2):447-57
references.pmid: 22105371
references.citation: Blood. 2009 Jul 16;114(3):702-8
references.pmid: 19470693
references.citation: J Clin Oncol. 2000 Feb;18(3):537-46
references.pmid: 10653869
references.citation: Haematologica. 2005 Jan;90(1):86-93
references.pmid: 15642674
references.citation: Am J Transplant. 2008 Dec;8(12):2674-83
references.pmid: 19032228
references.citation: N Engl J Med. 1989 Jun 29;320(26):1731-5
references.pmid: 2543925
references.citation: Blood. 2004 Dec 1;104(12):3664-71
references.pmid: 15304389
references.citation: Blood. 2012 Jan 12;119(2):399-410
references.pmid: 22096237
references.citation: Blood. 2008 Aug 1;112(3):914-5
references.pmid: 18650467
references.citation: Science. 2002 Mar 15;295(5562):2097-100
references.pmid: 11896281
references.citation: Blood. 2001 Sep 1;98(5):1358-64
references.pmid: 11520783
references.citation: Semin Hematol. 1991 Jul;28(3):250-9
references.pmid: 1887253
references.citation: Blood. 1990 Jun 15;75(12):2459-64
references.pmid: 2350582
references.citation: Bone Marrow Transplant. 2014 Mar;49(3):324-31
references.pmid: 23872737
references.citation: Blood. 2010 May 27;115(21):4293-301
references.pmid: 20233969
references.citation: J Immunol. 2012 Nov 15;189(10):5082-8
references.pmid: 23077239
references.citation: Korean J Pediatr. 2013 Jan;56(1):26-31
references.pmid: 23390442
references.citation: Biol Blood Marrow Transplant. 2008 Mar;14(3):323-34
references.pmid: 18275899
references.citation: J Infect Dis. 2008 Sep 15;198(6):818-26
references.pmid: 18666855
references.citation: Int J Hematol. 2010 May;91(4):588-95
references.pmid: 20414753
references.citation: Clin Infect Dis. 2009 Dec 15;49(12):1777-83
references.pmid: 19911937
references.citation: Viruses. 2009;1(3):362
references.pmid: 20151027
references.citation: J Virol Methods. 2007 Dec;146(1-2):147-54
references.pmid: 17673304
references.citation: AIDS Res Hum Retroviruses. 2012 Aug;28(8):844-51
references.pmid: 22074011
references.citation: J Clin Invest. 1998 May 1;101(9):1835-42
references.pmid: 9576746
references.citation: Proc Natl Acad Sci U S A. 2011 Sep 6;108(36):14725-32
references.pmid: 21825173
references.citation: J Clin Microbiol. 2013 Jul;51(7):2096-102
references.pmid: 23616450
references.citation: Transplantation. 2004 Jan 15;77(1):76-84
references.pmid: 14724439
references.citation: Front Immunol. 2013 Dec 13;4:458
references.pmid: 24379818
references.citation: Curr Opin Hematol. 2012 Jul;19(4):324-35
references.pmid: 22517587
references.citation: Eur J Immunol. 2012 Dec;42(12):3141-5
references.pmid: 23255011