A small molecule alpha 4 beta 1 antagonist prevents development of murine Lyme arthritis without affecting protective immunity.
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 alpha4beta1-dependent cell adhesion for the development of arthritis and for the antibacterial immune response. S16197 is shown to interfere specifically with the binding of alpha4beta(1 integrin to its ligands VCAM-1 and fibronectin in vitro. Treatment of B. burgdorferi-infected C3H/HeJ mice with the alpha4beta1 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 alpha4beta1-mediated influx of inflammatory cells. The onset of inflammation can be successfully targeted by treatment with S18407.
Gläsner
Joachim
J
Institute for Clinical Microbiology, Immunology, and Hygiene, University of Erlangen-Nürnberg, Erlangen, Germany.
Blum
Horst
H
Wehner
Volkmar
V
Stilz
Hans Ulrich
HU
Humphries
Jonathan D
JD
Curley
G Paul
GP
Mould
A Paul
AP
Humphries
Martin J
MJ
Hallmann
Rupert
R
Röllinghoff
Martin
M
Gessner
André
A
D000596:Amino Acids / Q000494:pharmacology*; D000818:Animals; D025065:Borrelia burgdorferi / Q000187:drug effects / Q000276:immunology; D002461:Cell Line, Transformed; D042783:Endothelial Cells / Q000276:immunology / Q000382:microbiology; D005260:Female; D005353:Fibronectins / Q000378:metabolism; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D007113:Immunity, Innate / Q000187:drug effects; D039041:Integrin alpha4beta1 / Q000037:antagonists & inhibitors*; D020014:K562 Cells; D007962:Leukocytes / Q000276:immunology; D008193:Lyme Disease / Q000188:drug therapy / Q000276:immunology / Q000503:physiopathology / Q000517:prevention & control*; D051379:Mice; D008809:Mice, Inbred C3H; D010671:Phenylurea Compounds / Q000494:pharmacology*; D011355:Prodrugs / Q000494:pharmacology; D013640:Tarsal Joints / Q000187:drug effects / Q000276:immunology / Q000382:microbiology / Q000503:physiopathology; D020298:U937 Cells; D019010:Vascular Cell Adhesion Molecule-1 / Q000378:metabolism
D000596:Amino Acids; D005353:Fibronectins; D007093:Imidazoles; D039041:Integrin alpha4beta1; D010671:Phenylurea Compounds; D011355:Prodrugs; C505442:S 16197; C505441:S 18407; D019010:Vascular Cell Adhesion Molecule-1