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A Small Molecule ₄₁ Antagonist Prevents Development of Murine Lyme Arthritis without Affecting Protective Immunity¹

Joachim Gläsner^*, Horst Blum, Volkmar Wehner, Hans Ulrich Stilz, Jonathan D. Humphries, G. Paul Curley, A. Paul Mould, Martin J. Humphries, Rupert Hallmann, Martin Röllinghoff^* and André Gessner^*,2

^* Institute for Clinical Microbiology, Immunology, and Hygiene, University of Erlangen-Nürnberg, Erlangen, Germany; Aventis Pharma Deutschland GmbH, a company of the Sanofi-Aventis Group, Frankfurt am Main, Germany; Wellcome Trust Centre for Cell-Matrix Research, Faculty of Life Sciences, University of Manchester, Manchester, United Kingdom; and Department of Experimental Pathology, University Hospital, Lund, Sweden

After infection with Borrelia burgdorferi, humans and mice under certain conditions develop arthritis. Initiation of inflammation is dependent on the migration of innate immune cells to the site of infection, controlled by interactions of a variety of adhesion molecules. In this study, we used the newly synthesized compound S18407, which is a prodrug of the active drug S16197, to analyze the functional importance of ₄₁-dependent cell adhesion for the development of arthritis and for the antibacterial immune response. S16197 is shown to interfere specifically with the binding of ₄₁ integrin to its ligands VCAM-1 and fibronectin in vitro. Treatment of B. burgdorferi-infected C3H/HeJ mice with the ₄₁ antagonist significantly ameliorated the outcome of clinical arthritis and the influx of neutrophilic granulocytes into ankle joints. Furthermore, local mRNA up-regulation of the proinflammatory mediators IL-1, IL-6, and cyclooxygenase-2 was largely abolished. Neither the synthesis of spirochete-specific Igs nor the development of a Th1-dominated immune response was altered by the treatment. Importantly, the drug also did not interfere with Ab-mediated control of spirochete load in the tissues. These findings demonstrate that the pathogenesis, but not the protective immune response, in Lyme arthritis is dependent on the ₄₁-mediated influx of inflammatory cells. The onset of inflammation can be successfully targeted by treatment with S18407.

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