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Cutting Edge: Natalizumab Blocks Adhesion but Not Initial Contact of Human T Cells to the Blood-Brain Barrier In Vivo in an Animal Model of Multiple Sclerosis¹

Caroline Coisne^*, Wenxian Mao and Britta Engelhardt^2,*

^* Theodor Kocher Institute, University of Bern, Bern, Switzerland; and Elan Pharmaceuticals, South San Francisco, CA 94080

The humanized anti-₄ integrin Ab Natalizumab is an effective treatment for relapsing-remitting multiple sclerosis. Natalizumab is thought to exert its therapeutic efficacy by blocking the ₄ integrin-mediated binding of circulating immune cells to the blood-brain barrier (BBB). As ₄ integrins control other immunological processes, natalizumab may, however, execute its beneficial effects elsewhere. By means of intravital microscopy we demonstrate that natalizumab specifically inhibits the firm adhesion but not the rolling or capture of human T cells on the inflamed BBB in mice with acute experimental autoimmune encephalomyelitis (EAE). The efficiency of natalizumab to block T cell adhesion to the inflamed BBB was found to be more effective in EAE than in acute systemic TNF--induced inflammation. Our data demonstrate that ₄ integrin-mediated adhesion of human T cells to the inflamed BBB during EAE is efficiently blocked by natalizumab and thus provide the first direct in vivo proof of concept of this therapy in multiple sclerosis.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work has been supported by the National Multiple Sclerosis Society of the United States, the Swiss Multiple Sclerosis Society, and the Bern University Research Foundation. C.C. has been funded by the Fondation pour la Recherche Médicale, the Association pour la Recherche sur la Sclérose en Plaques, and the National Multiple Sclerosis Society.

² Address correspondence and reprint requests to Prof. Britta Engelhardt, Theodor Kocher Institute, University of Bern, Freiestrasse 1, CH-3012 Bern, Switzerland. E-mail address: bengel{at}tki.unibe.ch

³ Abbreviations used in this paper: MS, multiple sclerosis; BBB, blood-brain barrier; EAE, experimental autoimmune encephalomyelitis; TRITC, tetramethylrhodamine.

⁴ The online version of this article contains supplemental material.

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