By Nelson Chao, MD

2009-01-01

Dr. Chao indicated no relevant conflicts of interest.

Stern M, Ruggeri L, Mancusi A, et al. Survival after T-cell-depleted haploidentical stem cell transplantation is improved using the mother as donor. Blood. 2008;112:2990-5.

Childbirth is rightfully considered one of the great wonders of life. The complexity of it all, from the moment of conception (I guess even before that) to implantation, the tolerance to a growing foreign body, and the delivery process is nothing short of miraculous. Yet the impact of the pregnancy continues through adulthood. The transfer of maternal and fetal cells through the placenta leads to microchimerism in both individuals that can be long-lived. This microchimerism is thought to induce tolerance as well as possible autoimmune diseases. The postulated hyporesponsiveness from the fetomaternal chimerism is thought to arise from non-inherited maternal antigens (NIMAs) to which the fetus is exposed. This effect is most prominent in the influence of haplotypes in solid organ transplantation. In this setting, matching a pair of siblings to the inherited paternal haplotype and mismatching on the maternal side leads to a markedly better 10-year kidney graft survival rate. The hypothesis is that the modulation of the immune system of the recipient to NIMA during gestation could lead to a decrease in immune responses toward the NIMA.

The manuscript by Stern, et al. extends this observation to haploidentical stem cell transplantation. They postulate that this microchimerism found in the mother and child could influence the outcome of the procedure. This is different from NIMA described above for solid organs, as the mother is the haploidentical donor, and, therefore, the child carries the IMA. They analyzed, retrospectively, 118 young patients who received highly T-cell-depleted haploidentical grafts following an ablative regimen. Patients receiving grafts from their mothers had a more favorable risk profile. They found that there was an improved event-free survival (50.6% +/- 7.6% vs. 11.1% +/- 4.2%) in favor of those patients who received transplants from the mother rather than the father. Overall survival was also improved for these patients, regardless of the type of leukemia or gender of the recipient, and most pronounced in those patients treated in remission. The improved outcome was a result of lower relapse rate and treatment-related mortality. The incidence of engraftment was not affected, and the incidence of grade II-IV acute graft-versus-host disease (GVHD) was lower in the recipients of maternal donors but did not achieve statistical significance (p=0.09). There was a strong effect on survival, especially after the first six months if there was killer inhibitory receptor (KIR) ligand mismatch. Of note, there was not a similar effect from female haplotype mismatched sibling donors, suggesting again that this effect is different from NIMA observations in solid organ transplantation.

These are interesting observations that should be validated in a prospective manner. Since the survival advantage was irrespective of gender, simple minor histocompatibility difference related to H-Y antigen is unlikely. Possible explanations for the improved outcomes could be secondary to maternal memory T cells against paternal antigens leading to better graft-versus-leukemia effect (GVL), although, presumably, this should lead to more GVHD as well. Alternatively, the memory could be tolerance to paternal antigens, which were expressed on the fetus, leading to less GVL and GVHD. One possibility is natural killer (NK) memory cells. NK alloreactivity has been well described by this group of investigators, and this study confirms its importance. When restricted to diseases that are sensitive to NK alloreactivity (AML and pediatric ALL), NK alloreactivity had a stronger impact than maternal donors. In diseases thought to be resistant to NK alloreactivity, maternal donors had a stronger impact, suggesting perhaps other differences which are not yet well understood.

In summary, more work is necessary to understand this discrepancy between maternal and paternal donors, but this study presents exciting new data that may allow yet another step in the selection of optimal donors in haploidentical hematopoietic transplantation.

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