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Characteristics and influencing factors of CD19+ B cell reconstitution in patients following haploidentical/mismatched hematopoietic stem cell transplantation

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Abstract

In patients undergoing hematopoietic stem cell transplantation (HSCT), B cells exert important, prolonged effects that provide protection from infection. In this study, we analyzed characteristics and influencing factors of CD19+ B cell reconstitution in 83 patients who underwent unmanipulated haploidentical/mismatched blood and bone marrow transplantation. Of these patients, 45 % showed a normal CD19+ B cell count at +360 days. Factors associated with lower CD19+ B cell levels were as follows: aGVHD grades II–IV had a trend to affect CD19+ B cell reconstitution at +180 days; clinically extensive cGVHD was significantly associated with CD19+ B cell deficiency at +360 days and serum IgG level at +180 and +360 days; cytomegalovirus (CMV) infection occurred after +38 days was correlated with lower B cell level at both +90 and +360 days, while those occurred before +38 days did not show this effect; glucocorticoids used around +90 and +180 days was associated with lower CD19+ B cell levels at +90 and +360 days, respectively, especially in patients that did not experience extensive cGVHD. In contrast, the number of HLA-mismatched locus positively correlated with CD19+ B cell at +90 days and serum IgG level at +180 days. In conclusion, CD19+ B cell recovery after haploidentical/mismatched HSCT was mainly influenced by GVHD and/or its treatment, CMV infection that occurred later (after +38 days) and use of glucocorticoids. Improvement of B cell recovery is likely to be achieved through effective prophylaxis of GVHD, minimized use of glucocorticoids, and preemptive treatment of CMV infection occurring after +38 days. More HLA-mismatched loci may initiate a stronger humoral response toward alloantigens >180 days after HSCT, which may be beneficial for the eradication of minimal residual disease and protection from infection.

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References

  1. Ishaqi MK, Afzal S, Dupuis A, Doyle J, Gassas A. Early lymphocyte recovery post-allogeneic hematopoietic stem cell transplantation is associated with significant graft-versus-leukemia effect without increase in graft-versus-host disease in pediatric acute lymphoblastic leukemia. Bone Marrow Transplant. 2008;41(3):245–52.

    Article  PubMed  CAS  Google Scholar 

  2. Kumar S, Chen MG, Gastineau DA, Gertz MA, Inwards DJ, Lacy MQ, et al. Lymphocyte recovery after allogeneic bone marrow transplantation predicts risk of relapse in acute lymphoblastic leukemia. Leukemia. 2003;17(9):1865–70.

    Article  PubMed  CAS  Google Scholar 

  3. Pavletic ZS, Joshi SS, Pirruccello SJ, Tarantolo SR, Kollath J, Reed EC, et al. Lymphocyte reconstitution after allogeneic blood stem cell transplantation for hematologic malignancies. Bone Marrow Transplant. 1998;21(1):33–41.

    Article  PubMed  CAS  Google Scholar 

  4. Storek J, Espino G, Dawson MA, Storer B, Flowers ME, Maloney DG. Low B-cell and monocyte counts on day 80 are associated with high infection rates between days 100 and 365 after allogeneic marrow transplantation. Blood. 2000;96(9):3290–3.

    PubMed  CAS  Google Scholar 

  5. Corre E, Carmagnat M, Busson M, de Latour RP, Robin M, Ribaud P, et al. Long-term immune deficiency after allogeneic stem cell transplantation: B-cell deficiency is associated with late infections. Haematologica. 2010;95(6):1025–9.

    Article  PubMed  Google Scholar 

  6. Storek J, Geddes M, Khan F, Huard B, Helg C, Chalandon Y, et al. Reconstitution of the immune system after hematopoietic stem cell transplantation in humans. Semin Immunopathol. 2008;30(4):425–37.

    Article  PubMed  Google Scholar 

  7. Small TN, Keever CA, Weiner-Fedus S, Heller G, O’Reilly RJ, Flomenberg N. B-cell differentiation following autologous, conventional, or T-cell depleted bone marrow transplantation: a recapitulation of normal B-cell ontogeny. Blood. 1990;76(8):1647–56.

    PubMed  CAS  Google Scholar 

  8. Kook H, Goldman F, Padley D, Giller R, Rumelhart S, Holida M, et al. Reconstruction of the immune system after unrelated or partially matched T-cell-depleted bone marrow transplantation in children: immunophenotypic analysis and factors affecting the speed of recovery. Blood. 1996;88(3):1089–97.

    PubMed  CAS  Google Scholar 

  9. Storek J, Wells D, Dawson MA, Storer B, Maloney DG. Factors influencing B lymphopoiesis after allogeneic hematopoietic cell transplantation. Blood. 2001;98(2):489–91.

    Article  PubMed  CAS  Google Scholar 

  10. Huang XJ, Liu DH, Liu KY, Xu LP, Chen H, Han W, et al. Haploidentical hematopoietic stem cell transplantation without in vitro T-cell depletion for the treatment of hematological malignancies. Bone Marrow Transplant. 2006;38(4):291–7.

    Article  PubMed  Google Scholar 

  11. Lu DP, Dong L, Wu T, Huang XJ, Zhang MJ, Han W, et al. Conditioning including antithymocyte globulin followed by unmanipulated HLA-mismatched/haploidentical blood and marrow transplantation can achieve comparable outcomes with HLA-identical sibling transplantation. Blood. 2006;107(8):3065–73.

    Article  PubMed  CAS  Google Scholar 

  12. Xiao-Jun H, Lan-Ping X, Kai-Yan L, Dai-Hong L, Huan C, Wei H, et al. HLA-mismatched/haploidentical hematopoietic stem cell transplantation without in vitro T cell depletion for chronic myeloid leukemia: improved outcomes in patients in accelerated phase and blast crisis phase. Ann Med. 2008;40(6):444–55.

    Article  PubMed  Google Scholar 

  13. Liu DH, Huang XJ, Liu KY, Xu LP, Chen H, Han W, et al. Haploidentical hematopoietic stem cell transplantation without in vitro T cell depletion for treatment of hematological malignancies in children. Biol Blood Marrow Transplant. 2008;14(4):469–77.

    Article  PubMed  CAS  Google Scholar 

  14. Glucksberg H, Storb R, Fefer A, Buckner CD, Neiman PE, Clift RA, et al. Clinical manifestations of graft-versus-host disease in human recipients of marrow from HL-A-matched sibling donors. Transplantation. 1974;18(4):295–304.

    Article  PubMed  CAS  Google Scholar 

  15. Lee SJ, Vogelsang G, Flowers ME. Chronic graft-versus-host disease. Biol Blood Marrow Transplant. 2003;9(4):215–33.

    Article  PubMed  CAS  Google Scholar 

  16. Broers AE, van der Holt B, Haze S, Braakman E, Gratama JW, Lowenberg B, et al. A comparison of postengraftment infectious morbidity and mortality after allogeneic partially T cell-depleted peripheral blood progenitor cell transplantation versus T cell-depleted bone marrow transplantation. Exp Hematol. 2005;33(8):912–9.

    Article  PubMed  Google Scholar 

  17. Maury S, Mary JY, Rabian C, Schwarzinger M, Toubert A, Scieux C, et al. Prolonged immune deficiency following allogeneic stem cell transplantation: risk factors and complications in adult patients. Br J Haematol. 2001;115(3):630–41.

    Article  PubMed  CAS  Google Scholar 

  18. Chang YJ, Zhao XY, Huo MR, Xu LP, Liu DH, Liu KY, et al. Immune reconstitution following unmanipulated HLA-mismatched/haploidentical transplantation compared with HLA-identical sibling transplantation. J Clin Immunol. 2011;32(2):268–80.

    Article  PubMed  Google Scholar 

  19. Borghesi LA, Smithson G, Kincade PW. Stromal cell modulation of negative regulatory signals that influence apoptosis and proliferation of B lineage lymphocytes. J Immunol. 1997;159(9):4171–9.

    PubMed  CAS  Google Scholar 

  20. Morrissey P, Charrier K, Bressler L, Alpert A. The influence of IL-1 treatment on the reconstitution of the hemopoietic and immune systems after sublethal radiation. J Immunol. 1988;140(12):4204–10.

    PubMed  CAS  Google Scholar 

  21. Krenger W, Hill GR, Ferrara JL. Cytokine cascades in acute graft-versus-host disease. Transplantation. 1997;64(4):553–8.

    Article  PubMed  CAS  Google Scholar 

  22. Hill GR, Krenger W, Ferrara JL. The role of cytokines in acute graft-versus-host disease. Cytokines Cell Mol Ther. 1997;3(4):257–66.

    PubMed  CAS  Google Scholar 

  23. LeBien TW. Fates of human B-cell precursors. Blood. 2000;96(1):9–23.

    PubMed  CAS  Google Scholar 

  24. Okamoto T, Kanamaru A, Kakishita E, Nagai K. Stromal fibroblastic and hematopoietic progenitors in patients with graft-versus-host disease (GVHD). Int J Hematol. 1991;54(4):299–306.

    PubMed  CAS  Google Scholar 

  25. Garvy BA, Telford WG, King LE, Fraker PJ. Glucocorticoids and irradiation-induced apoptosis in normal murine bone marrow B-lineage lymphocytes as determined by flow cytometry. Immunology. 1993;79(2):270–7.

    PubMed  CAS  Google Scholar 

  26. Shono Y, Ueha S, Wang Y, Abe J, Kurachi M, Matsuno Y, et al. Bone marrow graft-versus-host disease: early destruction of hematopoietic niche after MHC-mismatched hematopoietic stem cell transplantation. Blood. 2010;115(26):5401–11.

    Article  PubMed  CAS  Google Scholar 

  27. Lonnqvist B, Ringden O, Ljungman P, Wahren B, Gahrton G. Reduced risk of recurrent leukemia in bone-marrow transplant recipients after cytomegalovirus-infection. Br J Haematol. 1986;63(4):671–9.

    Article  PubMed  CAS  Google Scholar 

  28. Jacobsen N, Keiding N, Ryder L, Ringden O, Lonnqvist B, Gahrton G, et al. Graft-versus-leukaemia activity associated with cytomegalovirus antibody positive bone marrow donors in acute myeloid leukaemia. Lancet. 1987;1(8530):456–7.

    Article  PubMed  CAS  Google Scholar 

  29. Jacobsen N, Badsberg JH, Lonnqvist B, Ringden O, Volin L, Rajantie J, et al. Graft-versus-leukaemia activity associated with CMV-seropositive donor, post-transplant CMV infection, young donor age and chronic graft-versus-host disease in bone marrow allograft recipients. The Nordic Bone Marrow Transplantation Group. Bone Marrow Transplant. 1990;5(6):413–8.

    PubMed  CAS  Google Scholar 

  30. Emery VC. Cytomegalovirus: recent progress in understanding pathogenesis and control. QJM. 2011;105(5):401–5.

    Article  PubMed  Google Scholar 

  31. Cobbs CS. Evolving evidence implicates cytomegalovirus as a promoter of malignant glioma pathogenesis. Herpesviridae. 2011;2(1):10.

    Article  PubMed  CAS  Google Scholar 

  32. Preiksaitis JK, Janowska-Wieczorek A. Persistence of cytomegalovirus in human long-term bone marrow culture: relationship to hemopoiesis. J Med Virol. 1991;35(2):76–84.

    Article  PubMed  CAS  Google Scholar 

  33. Steinberg HN, Anderson J Jr, Lim B, Chatis PA. Cytomegalovirus infection of the BS-1 human stroma cell line: effect on murine hemopoiesis. Virology. 1993;196(2):427–32.

    Article  PubMed  CAS  Google Scholar 

  34. Reddehase MJ, Dreher-Stumpp L, Angele P, Balthesen M, Susa M. Hematopoietic stem cell deficiency resulting from cytomegalovirus infection of bone marrow stroma. Ann Hematol. 1992;64(Suppl):A125–7.

    Article  PubMed  Google Scholar 

  35. Igarashi H, Medina KL, Yokota T, Rossi MI, Sakaguchi N, Comp PC, et al. Early lymphoid progenitors in mouse and man are highly sensitive to glucocorticoids. Int Immunol. 2005;17(5):501–11.

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

This work was supported by the Beiijng Science Foundation of China (Grant no. 7122193), Higher school specialized research fund for the doctoral program funding issue (Grant no. 20110001110039). This work was also supported by a research fund from the Ministry of Education for excellent doctorial candidates of China.

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Correspondence to Xiao-Jun Huang.

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M. Xie and H.-X. Fu contributed equally to this work.

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Xie, M., Fu, HX., Chang, YJ. et al. Characteristics and influencing factors of CD19+ B cell reconstitution in patients following haploidentical/mismatched hematopoietic stem cell transplantation. Int J Hematol 96, 109–121 (2012). https://doi.org/10.1007/s12185-012-1099-5

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  • DOI: https://doi.org/10.1007/s12185-012-1099-5

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