title: B-lymphopoiesis is stopped by mobilizing doses of G-CSF and is rescued by overexpression of the anti-apoptotic protein Bcl2.
abstract: Osteoblasts are necessary to B lymphopoiesis and mobilizing doses of G-CSF or cyclophosphamide inhibit osteoblasts, whereas AMD3100/Plerixafor does not. However, the effect of these mobilizing agents on B lymphopoiesis has not been reported. Mice (wild-type, knocked-out for TNF-α and TRAIL, or over-expressing Bcl-2) were mobilized with G-CSF, cyclophosphamide, or AMD3100. Bone marrow, blood, spleen and lymph node content in B cells was measured. G-CSF stopped medullar B lymphopoiesis with concomitant loss of B-cell colony-forming units, pre-pro-B, pro-B, pre-B and mature B cells and increased B-cell apoptosis by an indirect mechanism. Overexpression of the anti-apoptotic protein Bcl2 in transgenic mice rescued B-cell colony forming units and pre-pro-B cells in the marrow, and prevented loss of all B cells in marrow, blood and spleen. Blockade of endogenous soluble TNF-α with Etanercept, or combined deletion of the TNF-α and TRAIL genes did not prevent B lymphopoiesis arrest in response to G-CSF. Unlike G-CSF, treatments with cyclophosphamide or AMD3100 did not suppress B lymphopoiesis but caused instead robust B-cell mobilization. G-CSF, cyclophosphamide and AMD3100 have distinct effects on B lymphopoiesis and B-cell mobilization with: 1) G-CSF inhibiting medullar B lymphopoiesis without mobilizing B cells in a mechanism distinct from the TNF-α-mediated loss of B lymphopoiesis observed during inflammation or viral infections; 2) CYP mobilizing B cells but blocking their maturation; and 3) AMD3100 mobilizing B cells without affecting B lymphopoiesis. These results suggest that blood mobilized with these three agents may have distinct immune properties.
authors.affiliation: Mater Research at the Translational Research Institute, Woolloongabba, Queensland, Australia.
authors.forename: Ingrid G
authors.initials: IG
authors.lastname: Winkler
authors.forename: Linda J
authors.initials: LJ
authors.lastname: Bendall
authors.forename: Catherine E
authors.initials: CE
authors.lastname: Forristal
authors.forename: Falak
authors.initials: F
authors.lastname: Helwani
authors.forename: Bianca
authors.initials: B
authors.lastname: Nowlan
authors.forename: Valerie
authors.initials: V
authors.lastname: Barbier
authors.forename: Yi
authors.initials: Y
authors.lastname: Shen
authors.forename: Adam
authors.initials: A
authors.lastname: Cisterne
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Sedger
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Levesque
mesh_terms: D000818:Animals; D016175:B-Lymphocyte Subsets / Q000187:drug effects / Q000378:metabolism; D001596:Benzylamines; D001853:Bone Marrow / Q000187:drug effects; D000080027:Cyclams; D003520:Cyclophosphamide / Q000494:pharmacology; D015870:Gene Expression; D016179:Granulocyte Colony-Stimulating Factor / Q000008:administration & dosage*; D019650:Hematopoietic Stem Cell Mobilization; D006571:Heterocyclic Compounds / Q000494:pharmacology; D038041:Lymphopoiesis / Q000187:drug effects* / Q000235:genetics*; D008297:Male; D051379:Mice; D054448:Precursor Cells, B-Lymphoid / Q000187:drug effects* / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics*; D013154:Spleen / Q000187:drug effects; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors
chemical_list: D001596:Benzylamines; D000080027:Cyclams; D006571:Heterocyclic Compounds; D019253:Proto-Oncogene Proteins c-bcl-2; D014409:Tumor Necrosis Factor-alpha; D016179:Granulocyte Colony-Stimulating Factor; D003520:Cyclophosphamide; C088327:plerixafor