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Immune Recovery

Dendritic cell reconstitution is associated with relapse-free survival and acute GVHD severity in children after allogeneic stem cell transplantation

Bone Marrow Transplantation volume 50, pages 266–273 (2015)Cite this article

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Abstract

DCs are potent APCs and key regulators of innate and adaptive immunity. After allo-SCT, their reconstitution in the peripheral blood (PB) to levels similar to those in healthy individuals tends to be slow. We investigate the age- and sex-dependant immune reconstitution of myeloid (mDC) and plasmacytoid DC (pDC) in the PB of 45 children with leukaemia or myelodysplastic syndrome (aged 1–17 years, median 10) after allo-SCT with regard to relapse, acute GVHD (aGVHD) and relapse-free survival. Low pDC/μL PB up to day 60 post SCT are associated with higher incidence of moderate or severe aGVHD (P=0.035), whereas high pDC/μL PB up to day 60 are associated with higher risk of relapse (P<0.001). The time-trend of DCs/μL PB for days 0–200 is a significant predictor of relapse-free survival for both mDCs (P<0.001) and pDCs (P=0.020). Jointly modelling DC reconstitution and complications improves on these simple criteria. Compared with BM, PBSC transplants tend to show slower mDC/pDC reconstitution (P=0.001, 0.031, respectively), but have no direct effect on relapse-free survival. These results suggest an important role for both mDCs and pDCs in the reconstituting immune system. The inclusion of mDCs and pDCs may improve existing models for complication prediction following allo-SCT.

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References

  1. Passweg J, Baldomero H, Chapuis B, Leibundgut K, Schanz U, Gratwohl A et al. Haematopoietic stem cell transplantation in Switzerland. Report from the Swiss Transplant Working Group Blood and Marrow Transplantation (STABMT) Registry 1997-2003. Swiss Med Wkly 2006; 136: 50–58.

    CAS  PubMed  Google Scholar 

  2. Klingebiel T, Handgretinger R, Lang P, Bader P, Niethammer D . Haploidentical transplantation for acute lymphoblastic leukemia in childhood. Blood Rev 2004; 18: 181–192.

    Article  Google Scholar 

  3. Devine SM, Adkins DR, Khoury H, Brown R, Vij R . Recent advances in allogeneic hematopoietic stem-cell transplantation. J Lab Clin Med 2003; 141: 7–32.

    Article  CAS  Google Scholar 

  4. Koenig M, Huenecke S, Salzmann-Manrique E, Esser R, Quaritsch R, Steinhilber D et al. Multivariate analyses of immune reconstitution in children after allo-SCT: risk-estimation based on age-matched leukocyte sub-populations. Bone Marrow Transplant 2010; 45: 613–621.

    Article  CAS  Google Scholar 

  5. Banchereau J, Steinman RM . Dendritic cells and the control of immunity. Nature 1998; 392: 245–252.

    Article  CAS  Google Scholar 

  6. Palucka K, Banchereau J . Dendritic cells: a link between innate and adaptive immunity. J Clin Immunol 1999; 19: 12–25.

    Article  CAS  Google Scholar 

  7. Banchereau J, Briere F, Caux C, Davoust J, Lebecque S, Liu YJ et al. Immunobiology of dendritic cells. Annu Rev Immunol 2000; 18: 767–811.

    Article  CAS  Google Scholar 

  8. Teig N, Moses D, Gieseler S, Schauer U . Age-related changes in human blood dendritic cell subpopulations. Scand J Immunol 2002; 55: 453–457.

    Article  CAS  Google Scholar 

  9. Vakkila J, Thomson AW, Vettenranta K, Sariola H, Saarinen-Pihkala UM . Dendritic cell subsets in childhood and in children with cancer: relation to age and disease prognosis. Clin Exp Immunol 2004; 135: 455–461.

    Article  CAS  Google Scholar 

  10. Vuckovic S, Gardiner D, Field K, Chapman GV, Khalil D, Gill D et al. Monitoring dendritic cells in clinical practice using a new whole blood single-platform TruCOUNT assay. J Immunol Methods 2004; 284: 73–87.

    Article  CAS  Google Scholar 

  11. Heinze A, Elze MC, Kloess S, Ciocarlie O, Königs C, Betz S et al. Age-Matched Dendritic Cell Subpopulations Reference Values in Childhood. Scand J Immunol 2013; 77: 213–220.

    Article  CAS  Google Scholar 

  12. Ciocarlie O, Heinze A, Elze MC, Kloess S, Klingebiel T, Serban M et al. Myeloid and plasmacytoid dendritic cells: reference ranges in the peripheral blood of healthy children. Klin Paediatr 2013; 225: 354–356.

    Article  CAS  Google Scholar 

  13. Porta MDD, Rigolin GMM, Alessandrino EPP, Maiocchi M, Malcovati L, Vanelli L et al. Dendritic cell recovery after allogeneic stem-cell transplantation in acute leukemia: correlations with clinical and transplant characteristics. Eur J Haematol 2004; 72: 18–25.

    Article  Google Scholar 

  14. Vakkila J, Thomson AW, Hovi L, Vettenranta K, Saarinen-Pihkala UM . Circulating dendritic cell subset levels after allogeneic stem cell transplantation in children correlate with time post transplant and severity of acute graft-versus-host disease. Bone Marrow Transplant 2005; 35: 501–507.

    Article  CAS  Google Scholar 

  15. Mohty M, Blaise D, Faucher C, Bardou VJJ, Gastaut JAA, Viens P et al. Impact of plasmacytoid dendritic cells on outcome after reduced-intensity conditioning allogeneic stem cell transplantation. Leukemia 2005; 19: 1–6.

    Article  CAS  Google Scholar 

  16. Reddy V, Iturraspe JA, Tzolas AC, Meier-Kriesche HUU, Schold J, Wingard JR . Low dendritic cell count after allogeneic hematopoietic stem cell transplantation predicts relapse, death, and acute graft-versus-host disease. Blood 2004; 103: 4330–4335.

    Article  CAS  Google Scholar 

  17. Talarn C, Urbano-Ispizua A, Martino R, Pérez-Simón JAA, Batlle M, Herrera C et al. Kinetics of recovery of dendritic cell subsets after reduced-intensity conditioning allogeneic stem cell transplantation and clinical outcome. Haematologica 2007; 92: 1655–1663.

    Article  Google Scholar 

  18. Takebayashi M, Amakawa R, Tajima K, Miyaji M, Nakamura K, Ito T et al. Blood dendritic cells are decreased in acute graft-versus-host disease. Bone Marrow Transplant 2004; 33: 989–996.

    Article  CAS  Google Scholar 

  19. Fagnoni FF, Oliviero B, Giorgiani G, De Stefano P, Dehò A, Zibera C et al. Reconstitution dynamics of plasmacytoid and myeloid dendritic cell precursors after allogeneic myeloablative hematopoietic stem cell transplantation. Blood 2004; 104: 281–289.

    Article  CAS  Google Scholar 

  20. Eapen M, Horowitz MM, Klein JP, Champlin RE, Loberiza FR, Ringdén O et al. Higher mortality after allogeneic peripheral-blood transplantation compared with bone marrow in children and adolescents: the Histocompatibility and Alternate Stem Cell Source Working Committee of the International Bone Marrow Transplant Registry. J Clin Oncol 2004; 22: 4872–4880.

    Article  Google Scholar 

  21. Diaz MA, Gonzalez-Vicent M, Gonzalez ME, Verdeguer A, Martinez A, Perez-Hurtado M et al. Long-term outcome of allogeneic PBSC transplantation in pediatric patients with hematological malignancies: a report of the Spanish Working Party for Blood and Marrow Transplantation in Children (GETMON) and the Spanish Group for Allogeneic Peripheral Blood Transplantation (GETH). Bone Marrow Transplant 2005; 36: 781–785.

    Article  CAS  Google Scholar 

  22. Ziegler-Heitbrock L, Ancuta P, Crowe S, Dalod M, Grau V, Hart DN et al. Nomenclature of monocytes and dendritic cells in blood. Blood 2010; 116: e74–e80.

    Article  CAS  Google Scholar 

  23. Dzionek A, Fuchs A, Schmidt P, Cremer S, Zysk M, Miltenyi S et al. BDCA-2, BDCA-3, and BDCA-4: three markers for distinct subsets of dendritic cells in human peripheral blood. J Immunol 2000; 165: 6037–6046.

    Article  CAS  Google Scholar 

  24. Cravens PD, Hayashida K, Davis LS, Nanki T, Lipsky PE . Human peripheral blood dendritic cells and monocyte subsets display similar chemokine receptor expression profiles with differential migratory responses. Scand J Immunol 2007; 65: 514–524.

    Article  CAS  Google Scholar 

  25. Cole TJ, Green PJ . Smoothing reference centile curves: the LMS method and penalized likelihood. Stat Med 1992; 11: 1305–1319.

    Article  CAS  Google Scholar 

  26. Box GEP, Cox DR . An analysis of transformations. J R Stat Soc Series B 1964; 26: 211–252.

    Google Scholar 

  27. R Development Core Team R: A Language and Environment for Statistical Computing. Vienna, Austria, 2013. http://www.R-project.org/.

  28. Therneau TM, Grambsch PM . Modeling Survival Data: Extending the Cox Model. Springer: New York, USA, 2001.

    Google Scholar 

  29. Pinheiro J, Bates D, DebRoy S, Sarkar DR . Development Core Team. nlme: Linear and Nonlinear Mixed Effects Models. Vienna: Austria, 2013. http://cran.r-project.org/package=nlme.

    Google Scholar 

  30. Rizopoulos D . JM: An R Package for the Joint Modelling of Longitudinal and Time-to-Event Data. J Stat Softw 2010; 35: 1–33.

    Article  Google Scholar 

  31. Yee TW . The VGAM Package for Categorical Data Analysis. J Stat Softw 2010; 32: 1–34.

    Article  Google Scholar 

  32. Matthews JN, Altman DG, Campbell MJ, Royston P . Analysis of serial measurements in medical research. BMJ 1990; 300: 230–235.

    Article  CAS  Google Scholar 

  33. Przepiorka D, Weisdorf D, Martin P, Klingemann HG, Beatty P, Hows J et al. 1994 Consensus Conference on Acute GVHD Grading. Bone Marrow Transplant 1995; 15: 825–828.

    CAS  Google Scholar 

  34. Stare J, Perme MP, Henderson R . A measure of explained variation for event history data. Biometrics 2010; 67: 750–759.

    Article  Google Scholar 

  35. Henderson R, Diggle P, Dobson A . Joint modelling of longitudinal measurements and event time data. Biostatistics 2000; 1: 465–480.

    Article  CAS  Google Scholar 

  36. Rizopoulos D . Dynamic predictions and prospective accuracy in joint models for longitudinal and time-to-event data. Biometrics 2011; 67: 819–829.

    Article  Google Scholar 

  37. Auffermann-Gretzinger S, Lossos IS, Vayntrub TA, Leong W, Grumet FC, Blume KG et al. Rapid establishment of dendritic cell chimerism in allogeneic hematopoietic cell transplant recipients. Blood 2002; 99: 1442–1448.

    Article  CAS  Google Scholar 

  38. Arpinati M, Chirumbolo G, Urbini B, Martelli V, Stanzani M, Falcioni S et al. Use of anti-BDCA-2 antibody for detection of dendritic cells type-2 (DC2) in allogeneic hematopoietic stem cell transplantation. Bone Marrow Transplant 2002; 29: 887–891.

    Article  CAS  Google Scholar 

  39. Pichyangkul S, Endy TP, Kalayanarooj S, Nisalak A, Yongvanitchit K, Green S et al. A blunted blood plasmacytoid dendritic cell response to an acute systemic viral infection is associated with increased disease severity. J Immunol 2003; 171: 5571–5578.

    Article  CAS  Google Scholar 

  40. Hagendorens MM, Ebo DG, Schuerwegh AJ, Huybrechs A, Van Bever HP, Bridts CH et al. Differences in circulating dendritic cell subtypes in cord blood and peripheral blood of healthy and allergic children. Clin Exp Allergy 2003; 33: 633–639.

    Article  CAS  Google Scholar 

  41. Cseh A, Vasarhelyi B, Molnar K, Szalay B, Svec P, Treszl A et al. Immune phenotype in children with therapy-naïve remitted and relapsed Crohn's disease. World J Gastroenterol 2010; 16: 6001–6009.

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Maecker B, Mougiakakos D, Zimmermann M, Behrens M, Hollander S, Schrauder A et al. Dendritic cell deficiencies in pediatric acute lymphoblastic leukemia patients. Leukemia 2006; 20: 645–649.

    Article  CAS  Google Scholar 

  43. Morse MA, Rizzieri D, Stenzel TT, Hobeika AC, Vredenburgh JJ, Chao NJ et al. Dendritic cell recovery following nonmyeloablative allogeneic stem cell transplants. J Hematother Stem Cell Res 2002; 11: 659–668.

    Article  Google Scholar 

  44. Nachbaur D, Kircher B . Dendritic cells in allogeneic hematopoietic stem cell transplantation. Leuk Lymphoma 2005; 46: 1387–1396.

    Article  CAS  Google Scholar 

  45. Woltman AM, de Fijter JW, Kamerling SW, Paul LC, Daha MR, van Kooten C . The effect of calcineurin inhibitors and corticosteroids on the differentiation of human dendritic cells. Eur J Immunol 2000; 30: 1807–1812.

    Article  CAS  Google Scholar 

  46. Brehm C, Huenecke S, Esser R, Kloess S, Quaiser A, Betz S et al. Interleukin-2-stimulated natural killer cells are less susceptible to mycophenolate mofetil than non-activated NK cells: possible consequences for immunotherapy. Cancer Immunol Immunother 2014; 63: 821–833.

    Article  CAS  Google Scholar 

  47. Shimizu K, Fujii S, Fujimoto K, Kawa K, Yamada A, Kawano F . Tacrolimus (FK506) treatment of CD34+ hematopoietic progenitor cells promote the development of dendritic cells that drive CD4+ T cells toward Th2 responses. J Leukoc Biol 2000; 68: 633–640.

    CAS  PubMed  Google Scholar 

  48. Liu QFF, Liu C, Zhang Y, Sun J, Yi ZSS, Fan ZPP et al. Peripheral blood stem cell transplantation compared with bone marrow transplantation from unrelated donors in patients with leukemia: a single institutional experience. Blood Cells Mol Dis 2010; 45: 75–81.

    Article  CAS  Google Scholar 

  49. Nagler A, Labopin M, Shimoni A, Niederwieser D, Mufti GJ, Zander AR et al. Mobilized peripheral blood stem cells compared with bone marrow as the stem cell source for unrelated donor allogeneic transplantation with reduced-intensity conditioning in patients with acute myeloid leukemia in complete remission: an analysis from the Acute Leukemia Working Party of the European Group for Blood and Marrow Transplantation. Biol Blood Marrow Transplant 2012; 18: 1422–1429.

    Article  Google Scholar 

  50. Nagler A, Labopin M, Shimoni A, Mufti GJ, Cornelissen JJ, Blaise D et al. Mobilized peripheral blood stem cells compared with bone marrow from HLA-identical siblings for reduced-intensity conditioning transplantation in acute myeloid leukemia in complete remission: a retrospective analysis from the Acute Leukemia Working Party of EBMT. Eur J Haematol 2012; 89: 206–213.

    Article  Google Scholar 

  51. Zhang H, Chen J, Que W . Allogeneic peripheral blood stem cell and bone marrow transplantation for hematologic malignancies: meta-analysis of randomized controlled trials. Leuk Res 2012; 36: 431–437.

    Article  Google Scholar 

  52. Powles R, Mehta J, Kulkarni S, Treleaven J, Millar B, Marsden J et al. Allogeneic blood and bone-marrow stem-cell transplantation in haematological malignant diseases: a randomised trial. Lancet 2000; 355: 1231–1237.

    Article  CAS  Google Scholar 

  53. Singhal S, Powles R, Kulkarni S, Treleaven J, Sirohi B, Millar B et al. Comparison of marrow and blood cell yields from the same donors in a double-blind, randomized study of allogeneic marrow vs blood stem cell transplantation. Bone Marrow Transplant 2000; 25: 501–505.

    Article  CAS  Google Scholar 

  54. Blaise D, Kuentz M, Fortanier C, Bourhis JH, Milpied N, Sutton L et al. Randomized trial of bone marrow versus lenograstim-primed blood cell allogeneic transplantation in patients with early-stage leukemia: a report from the Société Française de Greffe de Moelle. J Clin Oncol 2000; 18: 537–546.

    Article  CAS  Google Scholar 

  55. Faucher C, Mohty M, Vey N, Gaugler B, Bilger K, Moziconnacci MJJ et al. Bone marrow as stem cell source for allogeneic HLA-identical sibling transplantation following reduced-intensity preparative regimen. Exp Hematol 2003; 31: 873–880.

    Article  Google Scholar 

  56. Díez-Campelo M, Pérez-Simón JA, Ocio EM, Castilla C, González-Porras JR, Sánchez-Guijo FM et al. CD34+cell dose and outcome of patients undergoing reduced-intensity-conditioning allogeneic peripheral blood stem cell transplantation. Leuk Lymphoma 2005; 46: 177–183.

    Article  Google Scholar 

  57. Orsini G, Legitimo A, Failli A, Massei F, Biver P, Consolini R . Enumeration of human peripheral blood dendritic cells throughout the life. Int Immunol 2012; 24: 347–356.

    Article  CAS  Google Scholar 

  58. Schumm M, Feuchtinger T, Pfeiffer M, Hoelle W, Bethge W, Ebinger M et al. Flow cytometry with anti HLA-antibodies: a simple but highly sensitive method for monitoring chimerism and minimal residual disease after HLA-mismatched stem cell transplantation. Bone marrow transplant 2007; 39: 767–773.

    Article  CAS  Google Scholar 

  59. Alizadeh M, Bernard M, Danic B, Dauriac C, Birebent B, Lapart C et al. Quantitative assessment of hematopoietic chimerism after bone marrow transplantation by real-time quantitative polymerase chain reaction. Blood 2002; 99: 4618–4625.

    Article  CAS  Google Scholar 

  60. Auffermann-Gretzinger S, Lossos IS, Vayntrub TA, Leong W, Grumet FC, Blume KG et al. Rapid establishment of dendritic cell chimerism in allogeneic hematopoietic cell transplant recipients. Blood 2002; 99: 1442–1448.

    Article  CAS  Google Scholar 

  61. Pihusch M, Boeck S, Hamann M, Pihusch V, Heller T, Diem H et al. Peripheral dendritic cell chimerism in allogeneic hematopoietic stem cell recipients. Transplantation 2005; 80: 843–849.

    Article  Google Scholar 

  62. Koehl U, Bochennek K, Zimmermann SY, Lehrnbecher T, Sorensen J, Esser R et al. Immune recovery in children undergoing allogeneic stem cell transplantation: absolute CD8+CD3+ count reconstitution is associated with survival. Bone Marrow Transplant 2007; 39: 269–278.

    Article  CAS  Google Scholar 

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Acknowledgements

Markus C Elze is supported by the University of Warwick’s Chancellor's Scholarship and a PhD Fellowship from the German National Academic Foundation. Oana Ciocarlie is supported by the EU grant FP7-People-2012-ITN-317013 NATURIMMUNE and in part by the German Ministry of Education (IFB-Tx), ref. no. 01E00802. Annekathrin Heinze was supported by the Kind-Philipp-Stiftung für Leukämieforschung.

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  1. M C Elze and O Ciocarlie: These authors contributed equally to this work.

  2. U Köhl and J L Hutton: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Statistics, University of Warwick, Coventry, UK

    M C Elze & J L Hutton

  2. Institute of Cellular Therapeutics, Integrated Research and Treatment Center Transplantation, Hannover Medical School, Hannover, Germany

    O Ciocarlie, S Kloess, T Gardlowski, R Esser & U Köhl

  3. Paediatrics Department, Victor Babes University of Medicine and Pharmacy, Timisoara, Romania

    O Ciocarlie & M Serban

  4. Pediatrics Department, University Hospital Frankfurt, Goethe University, Frankfurt am Main, Germany

    A Heinze, T Klingebiel, P Bader & S Huenecke

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Elze, M., Ciocarlie, O., Heinze, A. et al. Dendritic cell reconstitution is associated with relapse-free survival and acute GVHD severity in children after allogeneic stem cell transplantation. Bone Marrow Transplant 50, 266–273 (2015). https://doi.org/10.1038/bmt.2014.257

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