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Reconstitution of NK cell receptors influences NK activity and relapse rate after haploidentical transplantation of T and B cell depleted grafts in children

Department of Pediatric Hematology/Oncology, University Children's Hospital, Eberhard Karl’s University, Tuebingen, Germany

Correspondence: Dr. Matthias Pfeiffer, Department of Pediatric Hematology/Oncology, University Children's Hospital, Eberhard Karl's University, Tuebingen, Hoppe Seyler Str.1 D 72076 Tuebingen, Germany. Phone: international +49.70712983781. Fax: international +49.7071295480. E-Mail: Matthias.Pfeiffer{at}med.uni-tuebingen.de

ABSTRACT

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

Design and Methods: We analyzed reconstitution patterns of NK-receptors at different time intervals after haploidentical transplantation by multi-color-flow-cytometry. NK cell activity and ADCC 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 ADCC activity against neuroblastoma and leukemic blasts as early as day fourteen posttransplant. KIR reconstitution showed a predominance of KIR negative NK 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 NK cells with a constant KIR-pattern after haploidentical transplantation with T and B cell depleted grafts. Moreover, these NK cells can mediate ADCC and therefore may allow for an early use of antibodies against residual malignant cells.