title: Hematopoietic mobilization: Potential biomarker of response to natalizumab in multiple sclerosis.
abstract: OBJECTIVE
  To ascertain the mobilization from the bone marrow and the functional relevance of the increased number of circulating hematopoietic stem and progenitor cells (HSPC) induced by the anti-α-4 integrin antibody natalizumab in patients with multiple sclerosis (MS).
  
  
  METHODS
  We evaluated CD45(low)CD34+ HSPC frequency by flow cytometry in blood from 45 natalizumab-treated patients (12 of whom were prospectively followed during the first year of treatment as part of a pilot cohort and 16 prospectively followed for validation), 10 untreated patients with MS, and 24 healthy donors. In the natalizumab-treated group, we also assessed sorted HSPC cell cycle status, T- and B-lymphocyte subpopulation frequencies (n = 29), and HSPC differentiation potential (n = 10).
  
  
  RESULTS
  Natalizumab-induced circulating HSPC were predominantly quiescent, suggesting recent mobilization from the bone marrow, and were capable of differentiating ex vivo. Circulating HSPC numbers were significantly increased during natalizumab, but heterogeneously, allowing the stratification of mobilizer and nonmobilizer subgroups. Nonmobilizer status was associated with persistence of disease activity during treatment. The frequency of B cells and CD103+CD8+ regulatory T cells persistently increased, more significantly in mobilizer patients, who also showed a specific naive/memory B-cell profile.
  
  
  CONCLUSIONS
  The data suggest that natalizumab-induced circulating HSPC increase is the result of true mobilization from the bone marrow and has clinical and immunologic relevance. HSPC mobilization, associated with clinical remission and increased proportion of circulating B and regulatory T cells, may contribute to the treatment's mode of action; thus, HSPC blood counts could represent an early biomarker of responsiveness to natalizumab.
authors.affiliation: From the Department of Medicine, Division of Brain Sciences, Centre for Neuroscience, Wolfson Neuroscience Laboratories (M.M., R.N., O.M., P.A.M.), and the Department of Medicine, Division of Experimental Medicine, Centre for Haematology (F.D.), Imperial College London, UK; the Departments of Neurosciences (R.N., O.M.) and Imaging (J.S.L., A.D.W.), Imperial College Healthcare NHS Trust, London, UK; and the Biostatistics Unit, Department of Health Sciences (M.P.S.), University of Genoa, Italy.
authors.forename: Miriam
authors.initials: M
authors.lastname: Mattoscio
authors.affiliation: From the Department of Medicine, Division of Brain Sciences, Centre for Neuroscience, Wolfson Neuroscience Laboratories (M.M., R.N., O.M., P.A.M.), and the Department of Medicine, Division of Experimental Medicine, Centre for Haematology (F.D.), Imperial College London, UK; the Departments of Neurosciences (R.N., O.M.) and Imaging (J.S.L., A.D.W.), Imperial College Healthcare NHS Trust, London, UK; and the Biostatistics Unit, Department of Health Sciences (M.P.S.), University of Genoa, Italy.
authors.forename: Richard
authors.initials: R
authors.lastname: Nicholas
authors.affiliation: From the Department of Medicine, Division of Brain Sciences, Centre for Neuroscience, Wolfson Neuroscience Laboratories (M.M., R.N., O.M., P.A.M.), and the Department of Medicine, Division of Experimental Medicine, Centre for Haematology (F.D.), Imperial College London, UK; the Departments of Neurosciences (R.N., O.M.) and Imaging (J.S.L., A.D.W.), Imperial College Healthcare NHS Trust, London, UK; and the Biostatistics Unit, Department of Health Sciences (M.P.S.), University of Genoa, Italy.
authors.forename: Maria P
authors.initials: MP
authors.lastname: Sormani
authors.affiliation: From the Department of Medicine, Division of Brain Sciences, Centre for Neuroscience, Wolfson Neuroscience Laboratories (M.M., R.N., O.M., P.A.M.), and the Department of Medicine, Division of Experimental Medicine, Centre for Haematology (F.D.), Imperial College London, UK; the Departments of Neurosciences (R.N., O.M.) and Imaging (J.S.L., A.D.W.), Imperial College Healthcare NHS Trust, London, UK; and the Biostatistics Unit, Department of Health Sciences (M.P.S.), University of Genoa, Italy.
authors.forename: Omar
authors.initials: O
authors.lastname: Malik
authors.affiliation: From the Department of Medicine, Division of Brain Sciences, Centre for Neuroscience, Wolfson Neuroscience Laboratories (M.M., R.N., O.M., P.A.M.), and the Department of Medicine, Division of Experimental Medicine, Centre for Haematology (F.D.), Imperial College London, UK; the Departments of Neurosciences (R.N., O.M.) and Imaging (J.S.L., A.D.W.), Imperial College Healthcare NHS Trust, London, UK; and the Biostatistics Unit, Department of Health Sciences (M.P.S.), University of Genoa, Italy.
authors.forename: Jean S
authors.initials: JS
authors.lastname: Lee
authors.affiliation: From the Department of Medicine, Division of Brain Sciences, Centre for Neuroscience, Wolfson Neuroscience Laboratories (M.M., R.N., O.M., P.A.M.), and the Department of Medicine, Division of Experimental Medicine, Centre for Haematology (F.D.), Imperial College London, UK; the Departments of Neurosciences (R.N., O.M.) and Imaging (J.S.L., A.D.W.), Imperial College Healthcare NHS Trust, London, UK; and the Biostatistics Unit, Department of Health Sciences (M.P.S.), University of Genoa, Italy.
authors.forename: Adam D
authors.initials: AD
authors.lastname: Waldman
authors.affiliation: From the Department of Medicine, Division of Brain Sciences, Centre for Neuroscience, Wolfson Neuroscience Laboratories (M.M., R.N., O.M., P.A.M.), and the Department of Medicine, Division of Experimental Medicine, Centre for Haematology (F.D.), Imperial College London, UK; the Departments of Neurosciences (R.N., O.M.) and Imaging (J.S.L., A.D.W.), Imperial College Healthcare NHS Trust, London, UK; and the Biostatistics Unit, Department of Health Sciences (M.P.S.), University of Genoa, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Dazzi
authors.affiliation: From the Department of Medicine, Division of Brain Sciences, Centre for Neuroscience, Wolfson Neuroscience Laboratories (M.M., R.N., O.M., P.A.M.), and the Department of Medicine, Division of Experimental Medicine, Centre for Haematology (F.D.), Imperial College London, UK; the Departments of Neurosciences (R.N., O.M.) and Imaging (J.S.L., A.D.W.), Imperial College Healthcare NHS Trust, London, UK; and the Biostatistics Unit, Department of Health Sciences (M.P.S.), University of Genoa, Italy. p.muraro@imperial.ac.uk.
authors.forename: Paolo A
authors.initials: PA
authors.lastname: Muraro
mesh_terms: D000328:Adult; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000494:pharmacology*; D015415:Biomarkers / Q000097:blood; D005260:Female; D019650:Hematopoietic Stem Cell Mobilization; D006412:Hematopoietic Stem Cells / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D008297:Male; D009103:Multiple Sclerosis / Q000097:blood / Q000188:drug therapy* / Q000503:physiopathology; D000069442:Natalizumab; D011446:Prospective Studies; D012008:Recurrence; D016896:Treatment Outcome
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D015415:Biomarkers; D000069442:Natalizumab