Cord blood maternal microchimerism following unrelated cord blood transplantation


Cord blood transplantation (CBT) is associated with low risk of leukemia relapse. Mechanisms underlying antileukemia benefit of CBT are not well understood, however a previous study strongly but indirectly implicated cells from the mother of the cord blood (CB) donor. A fetus acquires a small number of maternal cells referred to as maternal microchimerism (MMc) and MMc is sometimes detectable in CB. From a series of 95 patients who underwent double or single CBT at our center, we obtained or generated HLA-genotyping of CB mothers in 68. We employed a technique of highly sensitive HLA-specific quantitative-PCR assays targeting polymorphisms unique to the CB mother to assay CB-MMc in patients post-CBT. After additional exclusion criteria, CB-MMc was evaluated at multiple timepoints in 36 patients (529 specimens). CB-MMc was present in seven (19.4%) patients in bone marrow, peripheral blood, innate and adaptive immune cell subsets, and was detected up to 1-year post-CBT. Statistical trends to lower relapse, mortality, and treatment failure were observed for patients with vs. without CB-MMc post-CBT. Our study provides proof-of-concept that maternal cells of the CB graft can be tracked in recipients post-CBT, and underscore the importance of further investigating CB-MMc in sustained remission from leukemia following CBT.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.


All prices are NET prices.

Fig. 1: Maternal microchimerism of the cord blood donor (CB-MMc) in patients who received double or single CB transplantation (CBT).
Fig. 2: Dynamics of maternal microchimerism of the cord blood donor (CB-MMc) in the seven patients who had positive results post-CB transplantation (post-CBT).
Fig. 3: Probability (cumulative incidence) of relapse, overall mortality, and treatment failure post-cord blood transplantation (CBT), with a follow-up of up to 8+ years (2920+ days).


  1. 1.

    Rocha V, Wagner JE, Sobocinski KA, Klein JP, Zhang MJ, Horowitz MM, et al. Graft-versus-host disease in children who have received a cord-blood or bone marrow transplant from an HLA-identical sibling. Eurocord and International Bone Marrow Transplant Registry Working Committee on Alternative Donor and Stem Cell Sources. N Engl J Med. 2000;342:1846–54.

    CAS  Article  Google Scholar 

  2. 2.

    Gragert L, Eapen M, Williams E, Freeman J, Spellman S, Baitty R, et al. HLA match likelihoods for hematopoietic stem-cell grafts in the U.S. registry. N Engl J Med. 2014;371:339–48.

    CAS  Article  Google Scholar 

  3. 3.

    Ruggeri A, Paviglianiti A, Gluckman E, Rocha V. Impact of HLA in cord blood transplantation outcomes. HLA. 2016;87:413–21.

    CAS  Article  Google Scholar 

  4. 4.

    Brunstein CG, Gutman JA, Weisdorf DJ, Woolfrey AE, Defor TE, Gooley TA, et al. Allogeneic hematopoietic cell transplantation for hematologic malignancy: relative risks and benefits of double umbilical cord blood. Blood. 2010;116:4693–9.

    CAS  Article  Google Scholar 

  5. 5.

    Milano F, Gooley T, Wood B, Woolfrey A, Flowers ME, Doney K, et al. Cord-blood transplantation in patients with minimal residual disease. N Engl J Med. 2016;375:944–53.

    Article  Google Scholar 

  6. 6.

    Barker J, Hanash A. Cord blood T cells are “completely different”. Blood. 2015;126:2778–9.

    CAS  Article  Google Scholar 

  7. 7.

    Hiwarkar P, Qasim W, Ricciardelli I, Gilmour K, Quezada S, Saudemont A, et al. Cord blood T cells mediate enhanced antitumor effects compared with adult peripheral blood T cells. Blood. 2015;126:2882–91.

    CAS  Article  Google Scholar 

  8. 8.

    Toffalori C, Zito L, Gambacorta V, Riba M, Oliveira G, Bucci G, et al. Immune signature drives leukemia escape and relapse after hematopoietic cell transplantation. Nat Med. 2019;25:603–11.

    CAS  Article  Google Scholar 

  9. 9.

    van Rood JJ, Scaradavou A, Stevens CE. Indirect evidence that maternal microchimerism in cord blood mediates a graft-versus-leukemia effect in cord blood transplantation. Proc Natl Acad Sci USA. 2012;109:2509–14.

    Article  Google Scholar 

  10. 10.

    Milano F, Nelson JL, Delaney C. Fetal maternal immunity and antileukemia activity in cord-blood transplant recipients. Bone Marrow Transplant. 2013;48:321–2.

    CAS  Article  Google Scholar 

  11. 11.

    Nelson JL. The otherness of self: microchimerism in health and disease. Trends Immunol. 2012;33:421–7.

    CAS  Article  Google Scholar 

  12. 12.

    Kinder JM, Stelzer IA, Arck PC, Way SS. Immunological implications of pregnancy-induced microchimerism. Nat Rev Immunol. 2017;17:483–94.

    CAS  Article  Google Scholar 

  13. 13.

    Kanaan SB, Gammill HS, Harrington WE, Rosa SCD, Stevenson PA, Forsyth AM, et al. Maternal microchimerism is prevalent in cord blood in memory T cells and other cell subsets, and persists post-transplant. OncoImmunology. 2017;6:e1311436.

    Article  Google Scholar 

  14. 14.

    Parikh SH, Mendizabal A, Benjamin CL, Komanduri KV, Antony J, Petrovic A, et al. A novel reduced-intensity conditioning regimen for unrelated umbilical cord blood transplantation in children with nonmalignant diseases. Biol Blood Marrow Transplant. 2014;20:326–36.

    Article  Google Scholar 

  15. 15.

    Delaney C, Milano F, Cicconi L, Othus M, Becker PS, Sandhu V, et al. Infusion of a non-HLA-matched ex-vivo expanded cord blood progenitor cell product after intensive acute myeloid leukaemia chemotherapy: a phase 1 trial. Lancet Haematol. 2016;3:e330–9.

    Article  Google Scholar 

  16. 16.

    Milano F, Gammill H, Oliver DC, Kanaan SB, Nelson JL, Delaney C. Persistence of the losing cord blood unit following double cord blood transplantation: finding the unseen. Blood. 2017;130:1480–2.

    CAS  Article  Google Scholar 

  17. 17.

    Pillay J, den Braber I, Vrisekoop N, Kwast LM, de Boer RJ, Borghans JAM, et al. In vivo labeling with 2H2O reveals a human neutrophil lifespan of 5.4 days. Blood. 2010;116:625–7.

    CAS  Article  Google Scholar 

  18. 18.

    Kanaan SB, Sensoy O, Yan Z, Gadi VK, Richardson ML, Nelson JL. Immunogenicity of a rheumatoid arthritis protective sequence when acquired through microchimerism. Proc Natl Acad Sci USA. 2019;116:19600–8.

    CAS  Article  Google Scholar 

  19. 19.

    Lambert NC, Erickson TD, Yan Z, Pang JM, Guthrie KA, Furst DE, et al. Quantification of maternal microchimerism by HLA-specific real-time polymerase chain reaction: studies of healthy women and women with scleroderma. Arthritis Rheumatism. 2004;50:906–14.

    CAS  Article  Google Scholar 

  20. 20.

    Saiki RK, Gelfand DH, Stoffel S, Scharf SJ, Higuchi R, Horn GT, et al. Primer-directed enzymatic amplification of DNA with a thermostable DNA polymerase. Science. 1988;239:487–91.

    CAS  Article  Google Scholar 

  21. 21.

    Newcombe RG. Two-sided confidence intervals for the single proportion: comparison of seven methods. Stat Med. 1998;17:857–72.

    CAS  Article  Google Scholar 

  22. 22.

    Guthrie KA, Gammill HS, Kamper-Jørgensen M, Tjønneland A, Gadi VK, Nelson JL, et al. Statistical methods for unusual count data: examples from studies of microchimerism. Am J Epidemiol. 2016;184:779–86.

  23. 23.

    Loubiere LS, Lambert NC, Flinn LJ, Erickson TD, Yan Z, Guthrie KA, et al. Maternal microchimerism in healthy adults in lymphocytes, monocyte//macrophages and NK cells. Lab Invest. 2006;86:1185–92.

    CAS  Article  Google Scholar 

  24. 24.

    Mold JE, Michaëlsson J, Burt TD, Muench MO, Beckerman KP, Busch MP, et al. Maternal alloantigens promote the development of tolerogenic fetal regulatory T cells in utero. Science. 2008;322:1562–5.

    CAS  Article  Google Scholar 

  25. 25.

    Lo ES, Lo YM, Hjelm NM, Thilaganathan B. Transfer of nucleated maternal cells into fetal circulation during the second trimester of pregnancy. Br J Haematol. 1998;100:605–6.

    CAS  Article  Google Scholar 

  26. 26.

    Petit T, Dommergues M, Socié G, Dumez Y, Gluckman E, Brison O. Detection of maternal cells in human fetal blood during the third trimester of pregnancy using allele-specific PCR amplification. Br J Haematol. 1997;98:767–71.

    CAS  Article  Google Scholar 

  27. 27.

    Maloney S, Smith A, Furst DE, Myerson D, Rupert K, Evans PC, et al. Microchimerism of maternal origin persists into adult life. J Clin Invest. 1999;104:41–7.

    CAS  Article  Google Scholar 

  28. 28.

    Sunku Cuddapah C, Gadi V, deLavaldeLacoste B, Guthrie K, Nelson J. Maternal and fetal microchimerism in granulocytes. Chimerism. 2010;1:11–4.

    Article  Google Scholar 

  29. 29.

    Hall JM, Lingenfelter P, Adams SL, Lasser D, Hansen JA, Bean MA. Detection of maternal cells in human umbilical cord blood using fluorescence in situ hybridization. Blood. 1995;86:2829–32.

    CAS  Article  Google Scholar 

  30. 30.

    Melief CJM. “License to kill” reflects joint action of CD4 and CD8 T cells. Clin Cancer Res. 2013;19:4295–6.

    CAS  Article  Google Scholar 

  31. 31.

    Bracamonte-Baran W, Florentin J, Zhou Y, Jankowska-Gan E, Haynes WJ, Zhong W, et al. Modification of host dendritic cells by microchimerism-derived extracellular vesicles generates split tolerance. Proc Natl Acad Sci USA. 2017;114:1099–104.

    CAS  Article  Google Scholar 

Download references


This research was supported by the National Institutes of Health grant R01HL117737. The authors are grateful to the patients and families who consented to participate in the study.

Author information




JLN conceived the study, SBK, and JLN designed the experiments. SBK, OS, EK, AMF, and EC performed the experiments. Resources for the study including samples from cord blood mothers and study subject recruitment was accomplished by JA. SBK, CD, FM, AS, KVB, LAT, JA, NCL, and JLN analyzed the data and/or provided helpful comments and critical review. SBK wrote the paper.

Corresponding author

Correspondence to Sami B. Kanaan.

Ethics declarations

Conflict of interest

SBK and JLN are co-founders of Chimerocyte, Inc. that develops highly sensitive chimerism analysis technologies. Chimerocyte, Inc. had no role in funding this research project.

Additional information

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary information

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Kanaan, S.B., Delaney, C., Milano, F. et al. Cord blood maternal microchimerism following unrelated cord blood transplantation. Bone Marrow Transplant (2020).

Download citation


Quick links