Journal Article

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

Ordemann, R, Ziemssen, T, Reichmann, H, Oelschlaegel, U, Ehninger, G, Bornhäuser, M, Jing, D, Hölig, K

2010

Overview

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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 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 / Monoclonal antibodies / 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