A small molecule alpha(4)beta(1) antagonist prevents development of murine Lyme arthritis without affecting protective immunity

J Glasner, H Blum, V Wehner, H U Stilz, J D Humphries, G P Curley, A P Mould, M J Humphries, Rupert Hallmann, M Rollinghoff, A Gessner

Research output: Contribution to journalArticlepeer-review

13 Citations (SciVal)

Abstract

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 alpha(4)beta(1)-dependent cell adhesion for the development of arthritis and for the antibacterial immune response. S16197 is shown to interfere specifically with the binding of alpha(4)beta(1) integrin to its ligands VCAM-1 and fibronectin in vitro. Treatment of B. burgdorferi-infected C3H/Hej mice with the alpha(4)beta(1), 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 alpha(4)beta(1)-mediated influx of inflammatory cells. The onset of inflammation can be successfully targeted by treatment with S18407.
Original languageEnglish
Pages (from-to)4724-4734
JournalJournal of Immunology
Volume175
Issue number7
Publication statusPublished - 2005

Bibliographical note

The information about affiliations in this record was updated in December 2015.
The record was previously connected to the following departments: Pathology, (Lund) (013030000)

Subject classification (UKÄ)

  • Immunology in the medical area

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