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Apoptosis-susceptibility prolongs the lack of memory B cells in acute leukemic patients after allogeneic hematopoietic stem cell transplantation

Authors

  • A. Mensen
  • Y. Oh
  • S.C. Becker
  • P.G. Hemmati
  • C. Jehn
  • J. Westermann
  • M. Szyska
  • H. Göldner
  • B. Dörken
  • C. Scheibenbogen
  • R. Arnold
  • I.K. Na

Journal

  • Biology of Blood and Marrow Transplantation

Citation

  • Biol Blood Marrow Transplant 21 (11): 1895-1906

Abstract

  • Long-term survival after allogeneic hematopoietic stem cell transplantation requires an intact immunosurveillance, which howeverbut is hampered by conditioning therapy-associated lymphoid organ damage associated with conditioning therapy, by graft-versus-host disease and by immunosuppression. Our study aimed at identifying mechanisms contributing to sustained low memory B-cell numbers deficiency post-transplant. Peripheral B- and T-cell subset recovery and functional marker expression were investigated in 35 acute leukemic patients up to one year post-transplant. Apoptosis of B cells after CpG/CD40L/PMA/ionomycinBCR-independent and dependent stimulation and drug-efflux capacity were analysed. Half the patients suffered from infections post day 180. All patients were lackinghad strongly diminished CD27(+) memory B cells despite already normalized total B-cell numbers and fully-recovered CD27(-)IgD(-) memory B cells, putatively of extra-follicular origin. Circulating memory follicular helper T cells were reduced in the majority of patients as well. Naïve B cells exhibited a decreased expression of CXCR5, which mediates follicular B-cell entry. Additionally, a lower HLA-DR expression was found on naïve B cells, impairing antigen presentation. Upon T-cellCD40/TLR-9 dependent activation, B cells underwent significantly increased apoptosis (healthy 15±2%, patients 60±6%; p≤0.001) paralleled by an aberrant up-regulation of Fas-L on activated T cells and Fas on resting B cells. Significantly increased B-cell apoptosis was also observed after CD40/BCR and CD40/BCR/TLR-9 dependent activation. Drug-efflux capacity of naïve B cells was diminished in Cyclosporin A-treated patients, additionally contributing to an apoptosis-prone phenotype. We conclude that sustained B-cell survival, migration and T-cell communication defects are contributing candidates for an impaired germinal center formation of memory B cells after allogeneic hematopoietic stem cell transplantation. Follow-up studies should evaluate effectiveness of revaccinations on cellular level and should address the long-term sequela of B-cell defects post-transplant.


DOI

doi:10.1016/j.bbmt.2015.08.008