CD49d blockade by natalizumab in patients with multiple sclerosis affects steady-state hematopoiesis and mobilizes progenitors with a distinct phenotype and function.
Therapeutic application of natalizumab, an anti-CD49d Ab, in patients with multiple sclerosis (MS) has been associated with increased levels of circulating CD34+ progenitors. We analyzed the frequency, phenotype and functional activity of CD34+ HSC in blood and BM of patients with MS who were treated with natalizumab. Compared with healthy controls and untreated MS patients, natalizumab treatment increased CD34+ cells in the peripheral blood 7-fold and in BM 10-fold. CD34+ cells derived from blood and marrow of natalizumab-treated patients expressed less of the stem cell marker CD133, were enriched for erythroid progenitors (CFU-E) and expressed lower levels of adhesion molecules than G-CSF-mobilized CD34+ cells. The level of surface CXCR-4 expression on CD34+ cells from patients treated with natalizumab was higher compared with that of CD34+ cells mobilized by G-CSF (median 43.9 vs 15.1%). This was associated with a more than doubled migration capacity toward a chemokine stimulus. Furthermore, CD34+ cells mobilized by natalizumab contained more mRNA for p21 and less for matrix metallopeptidase 9 compared with G-CSF-mobilized hematopoietic stem cell (HSC). Our data indicate that G-CSF and CD49d blockade mobilize different HSC subsets and suggest that both strategies may be differentially applied in specific cell therapy approaches.
Jing
D
D
Department of Hematology and Oncology, University Hospital Dresden, Dresden, Germany.
Oelschlaegel
U
U
Ordemann
R
R
Hölig
K
K
Ehninger
G
G
Reichmann
H
H
Ziemssen
T
T
Bornhäuser
M
M
D000071916:AC133 Antigen; D000328:Adult; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D015703:Antigens, CD / Q000378:metabolism; D018952:Antigens, CD34 / Q000097:blood / Q000378:metabolism; D001854:Bone Marrow Cells / Q000378:metabolism; D002465:Cell Movement / Q000187:drug effects; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000235:genetics / Q000378:metabolism; D015672:Erythroid Precursor Cells / Q000187:drug effects* / Q000502:physiology; D005260:Female; D006023:Glycoproteins / Q000378:metabolism; D006410:Hematopoiesis / Q000187:drug effects*; D019650:Hematopoietic Stem Cell Mobilization; D006412:Hematopoietic Stem Cells / Q000187:drug effects / Q000502:physiology; D006706:Homeostasis; D006801:Humans; D016130:Immunophenotyping; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D039441:Integrin alpha4 / Q000276:immunology*; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D009103:Multiple Sclerosis / Q000097:blood / Q000188:drug therapy* / Q000378:metabolism; D000069442:Natalizumab; D010455:Peptides / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism
D000071916:AC133 Antigen; D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D015703:Antigens, CD; D018952:Antigens, CD34; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D006023:Glycoproteins; D007166:Immunosuppressive Agents; D000069442:Natalizumab; C000606023:PROM1 protein, human; D010455:Peptides; D012333:RNA, Messenger; D039441:Integrin alpha4; D020780:Matrix Metalloproteinase 9