Figure provided by Dr. Kanaan.
Human umbilical cord blood (CB) represents a source of hematopoietic stem cells when performing transplantation to treat patients affected by blood cell diseases such as cancer or inherited genetic disorders. CB is advantageous as it can be easily obtained, and in most cases does not require the donor and the recipient to be as rigorously genetically matched as in the other sources. However, few data are available regarding CB composition and the presence of maternal cells.
Cell exchange between the mother and the fetus happens during pregnancy. Maternal cells present in the CB in small numbers give rise to Maternal microchimerism (MMc). MMc persists for decades in the offspring and mother (1). Whether MMc can also be found in the recipient following CB transplantation has not been determined. Indirect evidence suggest that MMc from the donor CB might lead to graft-versus-leukemia effect, a phenomenon associated with hematopoietic stem cell transplant when the donor cells recognize and eliminate the leukemic recipient cells.
Dr. Sami B. Kanaan, a senior post-doctoral research fellow in the group of Dr. J. Lee Nelson (Clinical Research Division), in collaboration with Drs. Delaney and De Rosa, investigated MMc in CB and its implications for hematopoietic stem cell transplant. The results of their study were recently published in the journal Oncoimmunology.
The authors investigated the composition of maternal cells in CB from healthy pregnancies. To this end, 52 mother-CB pairs were studied for MMc prevalence and cell phenotypes in CB. Specific regions of the genomes were analyzed by sequencing and selected to allow the distinction between maternal and fetal cells based on distinct single nucleotide polymorphisms in the HLA, GSTT1, TG, ATIII and TNN genes.
Overall, MMc was detected in more than half of the analyzed CB (53%). Among the 27 CB that were further analyzed for MMc, 85% contained at least one cell lineage positive for MMc. Specifically, MMc was detected in memory T cells (51.9%), naïve T cells (40.7%), B cells (33.3%), Natural Killer (NK) cells (44.4%) and monocytes (55.6%), indicating that maternal hematopoietic cells are significantly represented in all the lineages. Quantitatively, MMc was consistently 28 to 60 times more abundant in memory T cells versus naïve T, B, NK cells, and monocytes. After the authors had normalized the amount of MMc in each cell lineage based on their proportional distribution in CB to obtain an adjusted MMc quantification, maternal memory T cells remained the most prevalent cell type, followed by maternal naïve T cells, compared to B cells, NK cells, and monocytes. Naïve T cells are a type of cell that has never encountered an antigen, while memory cells are long-lived antigen educated cells. The authors were interested in distinguishing between these two cell subsets because of the acknowledged central role that mature T cells play in the mediation of graft-versus-host and graft-versus-leukemia effects.
In the second part of the study, MMc was detected in a transplanted recipient previously treated with a double cord blood transplant for acute pre-B cell leukemia, after receiving Chimeric Antigen Receptor therapy as well as chemotherapy. This patient showed no signs of relapse one year after transplant. Peripheral blood cells were isolated from the patient and MMc was detected in T cells at 2 and 6 months post-transplant, as well as in monocytes and B cells at 3 months.
To summarize, MMc is naturally present across all cell lineages of CB, and is quantitatively more abundant in T cells, especially long-lived and antigen-educated memory T cells. MMc in T cells can persist in transplanted patients up to six months. The results also suggest that the number of maternal cells transferred to the transplanted individuals is sufficient to have an impact in vivo in the recipient. What can be the functional consequences of this transfer? Dr. Kanaan explained the implications of these observations: “The strongest indication that CB-originating MMc persisting post-transplant are functional, comes from a recent study in which significantly lower relapse probability of acute leukemia was observed post-CB transplantation when the paternally inherited human leukocyte antigens (HLA) of the CB, i.e. not present in the CB mother, were shared with the CB recipient, compared to when they were not (2)”.
When asked about future directions for the study, Dr. Kanaan answered: “Our next step will be investigating whether persistent CB-originating MMc is a common feature post-CB transplantation. An analysis in regard to patient outcomes (including: relapse rates, graft versus host disease, etc…) and of HLA-compatibility will likely give us insights into the role(s) and functional aspects of maternal cells that had time to be ‘educated’ against the paternally inherited HLA, now shared with the recipient. Currently major investment is being made in developing artificially-designed immunotherapies aimed at fighting leukemic cells. In this context, it seems especially important to also direct attention to understanding how naturally-acquired microchimeric cells may provide anti-leukemic benefit”.
This study was supported by the National Institutes of Health and the Trasher Research Fund.
Kanaan S.B., Gammill H.S., Harrington W.E., De Rosa S.C., Stevenson P.A., Forsyth A.M., Allen J., Cousin E., van Besien K., Delaney C.S., Nelson J.L. 2017. Maternal microchimerism is prevalent in cord blood in memory T cells and other cell subsets, and persists post-transplant. Oncoimmunology, 6(5):e1311436.
(1)- Maloney S, Smith A, Furst DE, MyersonD, Rupert K, Evans PC, Nelson JL. 1999. Microchimerism of maternal origin persists into adult life. The Journal in Clinical Investigation. 104(1):41-7.
(2)- Van Rood JJ, Scaravadou A, Stevens CE. 2012. Indirect evidence that maternal microchimerism in cord blood mediates a graft-versus-leukemia effect in cord blood transplantation. PNAS. 109(7):2509-14.