Influence of Fetomaternal Microchimerism on Maternal NK Cell Reactivity against the Child's Leukemic Blasts.

Ingo Müller,Lena-Marie Martin,Anne Kruchen,Boris Fehse

doi:10.3390/biomedicines10030603

Abstract

Persistence of fetal cells in the circulation of the mother (fetal microchimerism, FM) is associated with increased survival and reduced relapse of children with leukemia receiving a haploidentical hematopoietic stem cell transplantation (hHSCT). NK cells play an important role in maternal tolerance towards the unborn child. In this study, 70 mother–child pairs were prospectively analyzed for the occurrence of FM, KIR genotype and HLA-C type. We found that occurrence and level of FM were influenced by three maternal genetic factors: presence of an HLA-C1 allele, absence of KIR2DL3 and presence of a cen-B/B motif. Furthermore, an HLA-C match between mother and child favored persistence of FM. NK cells from FM+ mothers showed a 40% higher specific degranulation against their filial leukemic blasts than NK cells from FM− mothers, suggesting the presence of educated maternal NK cells. Nevertheless, cytotoxicity of parental NK cells against filial leukemic blasts was independent of KIR genetics (haplotype, B content score, centromeric and telomeric KIR gene regions) and independent of FM, indicating that additional immune effector mechanisms contribute to the beneficial effect of persisting FM in hHSCT.

Highlights

Haploidentical hematopoietic stem cell transplantation is well established for pediatric patients lacking an HLA-identical sibling and a matched-unrelated donor [1,2]
Cytotoxicity of parental NK cells against filial leukemic blasts was independent of killer immunoglobulin-like receptors (KIRs) genetics and independent of Fetomaternal microchimerism (FM), indicating that additional immune effector mechanisms contribute to the beneficial effect of persisting FM in Haploidentical hematopoietic stem cell transplantation (hHSCT)
We showed that persistent fetal microchimerism (FM+ ) in mothers, who donated stem cells for their children, was associated with an increased overall survival and reduced incidence of relapse, compared to father-to-child transplantations and transplantations from mothers without

Summary

Introduction

Haploidentical hematopoietic stem cell transplantation (hHSCT) is well established for pediatric patients lacking an HLA-identical sibling and a matched-unrelated donor [1,2]. Activating KIR genes in donors with a cen-B/B motif are associated with a better outcome in a cohort of adult and pediatric AML patients undergoing unrelated HSCT [32]. The presence of centromeric KIR B genes in the donor is associated with increased survival in HLA-identical sibling transplantations [34]. We investigated the role of NK cells in maintaining FM on the one hand and the effect of FM on the reactivity of maternal NK cells against leukemic blasts of their children on the other hand To this end, we analyzed the influence of maternal and filial HLA/KIR genes on the occurrence and level of FM and the impact of persisting FM on maternal NK cell KIR phenotype. The functionality of maternal NK cells against their child’s leukemic blasts was determined in vitro

Study Population

Cell Isolation and Treatment

DNA Isolation and Genotyping

Microchimerism Determination

Degranulation, KIR Phenotyping and Cytotoxicity Assay

Statistical and Flow Cytometry Data Analysis

Study Cohort

Effect of Filial Age and Sex on FM

Influence of HLA-C on FM

(Supplementary

Influence of FM on Parental NK Cell Reactivity

Discussion