Donor KIR3DL1/3DS1 gene and recipient Bw4 KIR ligand as prognostic markers for outcome in unrelated hematopoietic stem cell transplantation.
Given their antileukemic activity, natural killer (NK) cells can alter the outcome of hematopoietic stem cell transplantation (HSCT). The physiologic functions of NK cells are regulated by the interaction of killer immunoglobulin-like receptors (KIR) with specific HLA class I ligands. In the literature, different models based on HLA class I and/or KIR donor (D)/recipient (R) gene disparities are considered as predictors of NK cell alloreactivity. In this retrospective and multicentric French study, we analyzed the clinical impact of the different NK-alloreactivity models in 264 patients who underwent T repleted unrelated HSCT. First, we did not observe that the "KIR ligand-ligand" model had a significant clinical impact on unrelated HSCT outcome, whereas the "missing KIR ligand" model had a significant but limited effect on unrelated HSCT, because only the absence of C1 ligand in patients with myelogenous diseases was associated with a decreased overall survival (OS) (hazard ratio=2.17, P=.005). The "KIR receptor-receptor" and the "KIR receptor-ligand" models seemed the most capable of predicting NK alloreactivity because they had a significant impact on acute graft-versus-host disease (aGVHD) occurrence, OS, and relapse incidence in D/R unrelated pairs. In particular, KIR3DL1 gene mismatches in the GVH direction (D(+)R(-)) and the D KIR3DL1(+)/3DS1(+) and R Bw4(-) combination were respectively correlated with the lowest OS in HLA identical pairs (HR=1.99, P =.02) and the highest incidence of relapse in HLA nonidentical D/R unrelated pairs (HR=4.72, P =.03). Overall, our results suggest a detrimental effect of KIR3DL1(+)/3DS1(+) donor NK cells transplanted into HLA-Bw4(-) patients in the absence of an educational process via KIR3DL1/HLA-Bw4 interactions.
Gagne
Katia
K
Etablissement Français du Sang, Université de Nantes, Nantes Atlantique Universités, Immunovirologie et Polymorphisme génétique, EA4271, Nantes, France. katia.gagne@efs.sante.fr
Busson
Marc
M
Bignon
Jean-Denis
JD
Balère-Appert
Marie-Lorraine
ML
Loiseau
Pascale
P
Dormoy
Anne
A
Dubois
Valérie
V
Perrier
Pascale
P
Jollet
Isabelle
I
Bois
Monique
M
Masson
Dominique
D
Moine
Agnès
A
Absi
Léna
L
Blaise
Didier
D
Charron
Dominique
D
Raffoux
Colette
C
D000293:Adolescent; D000328:Adult; D015415:Biomarkers; D001855:Bone Marrow Diseases / Q000601:surgery; D002648:Child; D002675:Child, Preschool; D005260:Female; D005500:Follow-Up Studies; D015235:HLA-B Antigens / Q000032:analysis*; D019337:Hematologic Neoplasms / Q000601:surgery; D018380:Hematopoietic Stem Cell Transplantation; D006648:Histocompatibility; D006801:Humans; D007223:Infant; D007694:Killer Cells, Natural / Q000276:immunology*; D008024:Ligands; D019520:Living Donors; D008297:Male; D008875:Middle Aged; D018448:Models, Immunological; D011379:Prognosis; D054341:Receptors, KIR3DL1 / Q000235:genetics*; D054349:Receptors, KIR3DS1 / Q000235:genetics*; D012008:Recurrence; D012189:Retrospective Studies; D016019:Survival Analysis; D014184:Transplantation, Homologous / Q000276:immunology; D016896:Treatment Outcome; D055815:Young Adult
D015415:Biomarkers; D015235:HLA-B Antigens; C042388:HLA-Bw4 antigen; C515083:KIR3DL1 protein, human; D008024:Ligands; D054341:Receptors, KIR3DL1; D054349:Receptors, KIR3DS1