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

Item Type:Article
Title:Apoptosis-susceptibility prolongs the lack of memory B cells in acute leukemic patients after allogeneic hematopoietic stem cell transplantation
Creators Name:Mensen, A. and Oh, Y. and Becker, S.C. and Hemmati, P.G. and Jehn, C. and Westermann, J. and Szyska, M. and Göldner, H. and Dörken, B. and Scheibenbogen, C. and Arnold, R. and Na, I.K.
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.
Keywords:Allogeneic HSCT, B-Cell Intrinsic and Germinal Center Defects, Long-Term Memory B-Cell Paucity
Source:Biology of Blood and Marrow Transplantation
Page Range:1895-1906
Date:November 2015
Official Publication:https://doi.org/10.1016/j.bbmt.2015.08.008
PubMed:View item in PubMed

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