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Natalizumab disproportionately increases circulating pre-B and B cells in multiple sclerosis

From the Institute of Clinical Neuroimmunology (M.K., I.M., T.K., R.H., E.M.), Ludwig Maximilians University, Munich; and Department of Neuroimmunology (M.K., R.H., E.M.), Max Planck Institute of Neurobiology, Martinsried, Germany.

Address correspondence and reprint requests to Dr. Edgar Meinl, Department of Neuroimmunology, Max-Planck Institute of Neurobiology, Am Klopferspitz 18a, D-82152 Martinsried, Germany meinl{at}neuro.mpg.de

Background: Natalizumab, a humanized anti-4 integrin monoclonal antibody, reduces relapses and disease progression in patients with multiple sclerosis (MS). Whereas its presumed mode of action is inhibition of T cell/monocyte entry into the brain, little is known about its specific effect on B cells, which are increasingly recognized to participate in MS pathogenesis.

Methods: We obtained serial blood samples from 17 patients before and during natalizumab therapy for relapsing-remitting MS for up to 16 months, and blood samples from 10 untreated patients with MS and 13 healthy donors. We determined numbers of mature and immature lymphocyte subsets by flow cytometry for CD3, CD4, CD8, CD19, CD138, and CD10 in 111 samples. We analyzed marker transcripts for immature hematopoietic cells by quantitative PCR for CD34, Vpreβ1 (pre-B lymphocyte gene 1), and DNTT (terminal deoxynucleotidyltransferase) in 65 samples.

Results: Natalizumab therapy increased CD19⁺ mature B cells more than other lymphocytes/monocytes in blood (2.8-fold versus 1.3–1.8-fold increase in cells/µL; p < 0.01). Even greater was the increase of immature CD19⁺CD10⁺ pre-B cells (7.4-fold; p < 0.01). This pattern remained stable during treatment for up to 16 months. Transcripts of lymphocyte precursors (Vpreβ1 and DNTT) were elevated more than transcripts for CD34.

Conclusions: Circulating B cells and especially pre-B cells are most prominently elevated among the studied immune cell subsets, raising the possibility that the effects and side effects of natalizumab are partly mediated by actions on B cells.

Abbreviations: ANOVA = analysis of variance; MS = multiple sclerosis.

Supplemental data at www.neurology.org

Supported by the Hermann and Lilly Schilling Foundation, the Deutsche Forschungsgemeinschaft (DFG SFB 571), a grant from Biogen-Idec, and the Verein zur Therapieforschung für MS-Kranke.

Disclosure: R.H., E.M., and T.K. have received grant support and/or consultancy fees from Schering, Teva, Serono, and Biogen-Idec. The other authors report no conflicts of interest.

Received April 18, 2008. Accepted in final form July 15, 2008.

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