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

Glasner, J; Blum, H; Wehner, V; Stilz, H U; Humphries, J D; Curley, G P; Mould, A P; Humphries, M J; Hallmann, Rupert LU and Rollinghoff, M, et al. (2005) In Journal of Immunology 175(7). p.4724-4734
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),... (More)
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. (Less)
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Journal of Immunology
volume
175
issue
7
pages
4724 - 4734
publisher
American Association of Immunologists
external identifiers
  • wos:000232092600070
  • pmid:16177120
  • scopus:25444508682
ISSN
1550-6606
language
English
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yes
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c4185a22-875f-4a17-ad2f-a4c85ecc548b (old id 223088)
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http://www.jimmunol.org/cgi/content/full/175/7/4724
date added to LUP
2007-08-02 16:35:53
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2017-01-01 07:10:22
@article{c4185a22-875f-4a17-ad2f-a4c85ecc548b,
  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.},
  author       = {Glasner, J and Blum, H and Wehner, V and Stilz, H U and Humphries, J D and Curley, G P and Mould, A P and Humphries, M J and Hallmann, Rupert and Rollinghoff, M and Gessner, A},
  issn         = {1550-6606},
  language     = {eng},
  number       = {7},
  pages        = {4724--4734},
  publisher    = {American Association of Immunologists},
  series       = {Journal of Immunology},
  title        = {A small molecule alpha(4)beta(1) antagonist prevents development of murine Lyme arthritis without affecting protective immunity},
  volume       = {175},
  year         = {2005},
}