CD49d blockade by natalizumab in patients with multiple sclerosis affects steady-state hematopoiesis and mobilizes progenitors with a distinct phenotype and function

• Published in: Bone marrow transplantation (Basingstoke) Vol. 45; no. 10; pp. 1489 - 1496
• Main Authors: Jing, D, Oelschlaegel, U, Ordemann, R, Hölig, K, Ehninger, G, Reichmann, H, Ziemssen, T, Bornhäuser, M
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-10-2010; Nature Publishing Group
• Subjects: 631/136/532/1542; 631/80/84; 692/699/249/1313/1666; 692/700/565/1436; AC133 Antigen; Adult; Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy; Antibodies, Monoclonal - therapeutic use; Antibodies, Monoclonal, Humanized; Antigens, CD - metabolism; Antigens, CD34 - blood; Antigens, CD34 - metabolism; Biological and medical sciences; Blood; Bone marrow; Bone Marrow Cells - metabolism; Bone marrow, stem cells transplantation. Graft versus host reaction; CD34 antigen; CD49d antigen; Cell adhesion molecules; Cell Biology; Cell Movement - drug effects; Cell therapy; Cerebrospinal fluid; Chemokines; Cyclin-Dependent Kinase Inhibitor p21 - genetics; Cyclin-Dependent Kinase Inhibitor p21 - metabolism; Drug therapy; Erythroid Precursor Cells - drug effects; Erythroid Precursor Cells - physiology; Female; Frequency analysis; Glycoproteins - metabolism; Granulocyte colony-stimulating factor; Health aspects; Hematology; Hematopoiesis; Hematopoiesis - drug effects; Hematopoietic Stem Cell Mobilization; Hematopoietic stem cells; Hematopoietic Stem Cells - drug effects; Hematopoietic Stem Cells - physiology; Homeostasis; Humans; Immunophenotyping; Immunosuppressive Agents - therapeutic use; Integrin alpha4 - immunology; Internal Medicine; Male; Matrix Metalloproteinase 9 - genetics; Matrix Metalloproteinase 9 - metabolism; Matrix metalloproteinases; Medical sciences; Medicine; Medicine & Public Health; Metalloproteinase; mRNA; Multiple sclerosis; Multiple Sclerosis - blood; Multiple Sclerosis - drug therapy; Multiple Sclerosis - metabolism; Multiple sclerosis and variants. Guillain barré syndrome and other inflammatory polyneuropathies. Leukoencephalitis; Natalizumab; Neurology; original-article; Patients; Peptides - metabolism; Peripheral blood; Phenotypes; Progenitor cells; Public Health; Risk factors; RNA, Messenger - metabolism; Stem cell transplantation; Stem Cells; Transfusions. Complications. Transfusion reactions. Cell and gene therapy; Transplantation; Germany; hematopoietic stem and progenitor cells; migration; mobilization; G-CSF; natalizumab; Human; Nervous system diseases; Multiple sclerosis; Hematology; Natalizumab; Stem cell; α4 integrin; Hematopoietic cell; Monoclonal antibody; Inflammatory disease; Immunomodulator; Mobilization; Granulocyte colony stimulating factor; Phenotype; Hematopoiesis; Central nervous system disease; Cell migration
• ISSN: 0268-3369; 1476-5365
• DOI: 10.1038/bmt.2009.381

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.