Reconstitution of natural killer cell receptors influences natural killer activity and relapse rate after haploidentical transplantation of T- and B-cell depleted grafts in children.
BACKGROUND
Natural killer cells have been demonstrated to exert remarkable graft-versus-leukemia effects after haploidentical transplantation. Acquisition of both, inhibiting and activating, receptors on developing natural killer cells is an important step in their functional maturation. Here, we report on the reconstitution of natural killer receptors after haploidentical transplantation of T-and B-cell (CD3/CD19) depleted grafts with co-transfusion of natural killer cells in children and its influence on natural killer cell activity and clinical outcome.


METHODS
We analyzed reconstitution patterns of natural killer receptors at different time intervals after haploidentical transplantation by multi-color flow cytometry. Natural killer cell activity and antibody-dependent cellular cytotoxicity was tested against cell lines and leukemic blasts in vitro. Survival was analyzed using Kaplan-Meier estimates.


RESULTS
Recovery of CD56(+)/CD16(+) cells was fast with high cytolytic activity against K562 and strong antibody-dependent cellular cytotoxicity activity against neuroblastoma and leukemic blasts as early as day 14 posttransplant. KIR reconstitution showed a predominance of KIR negative natural killer cells early after transplantation and an early reconstitution of CD158b compared to CD158a and CD158e. These differences were independent of presence or absence of the corresponding KIR ligands in donors or recipients. This reconstitution pattern was associated with a higher relapse probability of patients homozygous for HLA-C1-alleles compared to patients homozygous or even heterozygous for HLA-C2-alleles.


CONCLUSIONS
Our results indicate a fast recovery of functional and alloreactive natural killer cells with a constant KIR pattern after haploidentical transplantation with T- and B-cell depleted grafts. Moreover, these natural killer cells can mediate antibody-dependent cellular cytotoxicity and therefore may allow for an early use of antibodies against residual malignant cells.
Pfeiffer
Matthias M
MM
Department of Pediatric Hematology/Oncology, University Children's Hospital, Eberhard Karl's University, Tuebingen, Germany. matthias.pfeiffer@med.uni-tuebingen.de
Feuchtinger
Tobias
T
Teltschik
Heiko-Manuel
HM
Schumm
Michael
M
Müller
Ingo
I
Handgretinger
Rupert
R
Lang
Peter
P
D000293:Adolescent; D000328:Adult; D000483:Alleles; D001402:B-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D017252:CD3 Complex / Q000276:immunology / Q000378:metabolism; D019002:CD56 Antigen / Q000276:immunology / Q000378:metabolism; D002648:Child; D002675:Child, Preschool; D003602:Cytotoxicity, Immunologic / Q000276:immunology; D005434:Flow Cytometry; D015236:HLA-C Antigens / Q000235:genetics / Q000276:immunology; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods*; D006801:Humans; D007223:Infant; D020014:K562 Cells; D007694:Killer Cells, Natural / Q000276:immunology* / Q000378:metabolism; D017452:Receptors, IgG / Q000276:immunology / Q000378:metabolism; D055607:Receptors, Natural Killer Cell / Q000276:immunology* / Q000378:metabolism; D012008:Recurrence; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D055815:Young Adult
D017252:CD3 Complex; D019002:CD56 Antigen; D015236:HLA-C Antigens; D017452:Receptors, IgG; D055607:Receptors, Natural Killer Cell