Fetomaternal Microchimerism Is Associated with Better Outcome in Haploidentical Hematopoietic Stem Cell Transplantation

Haploidentical hematopoietic stem cell transplantation (hHSCT) from a parent to a child has become well established for pediatric patients with high risk leukemia in the absence of an HLA-matched donor. Donor choice in hHSCT has been an issue addressed by several groups. Some showed a beneficial impact of certain Killer immunoglobulin-like receptor (KIR)/KIR ligand constellations in different transplantation settings. Others demonstrated an improved outcome after mother-to-child transplantations compared to father-to-child transplantations in terms of lower transplant-related mortality and lower incidence of graft-versus-host disease (GvHD). Obviously, pregnancy leaves an imprint on the mother’s immune system, which is beneficial in hHSCT from mother to child. During pregnancy, a fetal microchimerism (FM) is established in the mother by fetal cells crossing the placental barrier dividing maternal and fetal circulation. In some mothers, fetal cells can be detected in peripheral blood for more than three decades after birth. Yet, not all mothers develop a persisting FM. CD56^brightNK cells make up approximately 70% of the lymphocytes in the decidua during the first trimester of pregnancy and represent the major cell subset interacting with cells of the developing fetus. Not surprisingly, certain maternal KIR/fetal KIR ligand combinations are associated with recurrent spontaneous abortions or preeclampsia. We hypothesized that (i) FM plays a role in hHSCT, and that (ii) FM may be influenced by the KIR pattern on maternal NK cells and KIR ligands on the child’s cells.

In a multicenter retrospective study, we analyzed 46 pediatric patients from 6 German transplantation centers (Tübingen, Frankfurt, Düsseldorf, Heidelberg, Jena, and Hamburg) who underwent first T-cell depleted hHSCT from a parent following conditioning with fludarabine, thiotepa, melphalan and ATG for standard indications: acute lymphoblastic leukemia (n=10), acute myeloid leukemia (n=10), juvenile myelomonocytic leukemia (n=1), lymphoproliferative disease (n=2), myelodysplastic syndrome (n=4), hemophagocytic lymphohistiocytosis (n=3), immune deficiencies (n=9), and others (n=7). Excess DNA of the donors extracted from peripheral blood prior to transplantation was assayed for fetal DNA (in mother-to-child transplantations), and for KIR genotype by real-time PCR. Mothers who had at least one fetal cell within 250,000 maternal cells could be detected were considered as FM⁺. Although we confirmed that, overall mothers as a group are better donors than fathers, in closer analysis this held only true for FM⁺ mother. Overall survival was significantly higher in the group of patients receiving stem cells from their FM⁺ mother compared to the patients grafted from their FM¯ mother (72% vs. 29), or father (72% vs. 50%). Most interestingly, looking at the minimal residual disease (MRD) negative acute leukemia patients undergoing first allogeneic HSCT for standard indications, overall survival was also significantly higher after hHSCT from FM⁺ mothers than from FM¯ mothers (66% vs. 26%) and there was a trend towards lower risk of relapse in the FM⁺ group (25% vs. 52%). There was no case of grade IV acute GvHD and only one or no case of acute GvHD grade III in all groups. Percentages of grade I + II acute GvHD did not differ significantly among FM⁺and FM¯ groups.

Reasons for persistence of fetal cells in some, but not all mothers are controversial. While fetal microchimerism is detected during pregnancy and early after birth in almost all mothers, it is reported to decrease below the detection limit in many mothers over time. In our cohort, we found no correlation of FM with age or gender of the respective child. Since a poor outcome after hHSCT has been reported for patients that are homozygous for HLA-C1, we also grouped our cohort into a HLA-C1 heterozygous and a homozygous group. Interestingly, not only an improved outcome, but also a higher average FM could be seen in the HLA-C1 heterozygous group compared to the C1 homozygous group. Furthermore, mothers expressing KIR2DS1 showed a significantly higher level of FM compared to those negative for this activating KIR. These findings suggest a certain role for KIR and HLA-C on the persistence of fetal microchimerism in mothers.

In conclusion, detection of fetal microchimerism may contribute to identification of the most promising parental donor in haploidentical stem cell transplantation.