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Olaf Stüve, MD, PhD; Christina M. Marra, MD; Amit Bar-Or, MD; Masaaki Niino, MD; Petra D. Cravens, PhD; Sabine Cepok, PhD; Elliot M. Frohman, MD, PhD; J. Theodore Phillips, MD, PhD; Gabriele Arendt, MD; Keith R. Jerome, MD, PhD; Linda Cook, PhD; Francois Grand'Maison, MD; Bernhard Hemmer, MD; Nancy L. Monson, PhD; Michael K. Racke, MD

Arch Neurol. 2006;63:1383-1387.

Background  Treatment with natalizumab, a monoclonal antibody against the adhesion molecule very late activation antigen 4, an 4₁ integrin, was recently associated with the development of progressive multifocal leukoencephalopathy, a demyelinating disorder of the central nervous system caused by JC virus infection.

Objective  To test the effect of natalizumab treatment on the CD4⁺/CD8⁺ T-cell ratios in cerebrospinal fluid (CSF) and peripheral blood.

Design  Prospective longitudinal study.

Setting  Academic and private multiple sclerosis centers.

Patients  Patients with multiple sclerosis (MS) treated with natalizumab, untreated patients with MS, patients with other neurologic diseases, and human immunodeficiency virus–infected patients.

Main Outcome Measures  CD4⁺ and CD8⁺ T cells were enumerated in CSF and peripheral blood. The mean fluorescence intensity of unbound 4 integrin on peripheral blood CD4⁺ and CD8⁺ T cells was analyzed before and after natalizumab therapy.

Results  Natalizumab therapy decreased the CSF CD4⁺/CD8⁺ ratio of patients with MS to levels similar to those of human immunodeficiency virus–infected patients. CD4⁺/CD8⁺ ratios in peripheral blood in patients with MS progressively decreased with the number of natalizumab doses, but they remained within normal limits. Six months after the cessation of natalizumab therapy, CSF CD4⁺/CD8⁺ ratios normalized. The expression of unbound 4 integrin on peripheral blood T cells decreases with natalizumab therapy and was significantly lower on CD4⁺ vs CD8⁺ T cells.

Conclusions  Natalizumab treatment alters the CSF CD4⁺/CD8⁺ ratio. Lower expression of unbound 4 integrin on CD4⁺ T cells is one possible mechanism. These results may have implications for the observation that some natalizumab-treated patients with MS developed progressive multifocal leukoencephalopathy.

Author Affiliations: Department of Neurology (Drs Stüve, Cravens, Frohman, Monson, and Racke) and Center for Immunology (Drs Monson and Racke), University of Texas Southwestern Medical Center at Dallas; Neurology Section, VA North Texas Health Care System, Medical Service, Dallas (Dr Stüve); Departments of Neurology (Dr Marra) and Laboratory Medicine (Drs Jerome and Cook), University of Washington, Seattle; Department of Neurology and Neurosurgery, Montreal Neurological Institute (Drs Bar-Or and Niino), and Department of Microbiology and Immunology (Dr Bar-Or), McGill University, Montreal, Quebec; Fred Hutchinson Cancer Research Center, Seattle (Drs Jerome and Cook); Department of Neurology, Heinrich Heine University, Düsseldorf, Germany (Drs Stüve, Cepok, Arendt, and Hemmer); Multiple Sclerosis Center at Texas Neurology, Dallas (Dr Phillips); and MS Clinic l'Hôpital Charles LeMoyne, Montreal (Dr Grand'Maison).

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