An LFA-1 (alphaLbeta2) small-molecule antagonist reduces inflammation and joint destruction in murine models of arthritis.
JOURNAL OF IMMUNOLOGY(2010)
摘要
LFA-1 appears to play a central role in normal immune responses to foreign Ags. In autoimmune or inflammatory diseases, there is increased expression of LFA-1 and/or its counterligand, ICAM-1. Others have demonstrated that the targeted disruption of LFA-1:ICAM interactions, either by gene deletion or Ab treatment in mice, results in reduced leukocyte trafficking, inflammatory responses, and inhibition of inflammatory arthritis in the K/BxN serum transfer model. However, there has been little success in finding a small-molecule LFA-1 antagonist that can similarly impact rodent models of arthritis. In this paper, we present the first reported example of an LFA-1 small-molecule antagonist, BMS-587101, that is efficacious in preclinical disease models. In vitro, BMS-587101 inhibited LFA-1-mediated adhesion of T cells to endothelial cells, T cell proliferation, and Th1 cytokine production. Because BMS-587101 exhibits in vitro potency, cross-reactivity, and oral bioavailability in rodents, we evaluated the impact of oral administration of this compound in two different models of arthritis: Ab-induced arthritis and collagen-induced arthritis. Significant impact of BMS-587101 on clinical score in both models was observed, with inhibition comparable or better than anti-mouse LFA-1 Ab. In addition, BMS-587101 significantly reduced cytokine mRNA levels in the joints of Ab-induced arthritis animals as compared with those receiving vehicle alone. In paws taken from the collagen-induced arthritis study, the bones of vehicle-treated mice had extensive inflammation and bone destruction, whereas treatment with BMS-587101 resulted in marked protection. These findings support the potential use of an LFA-1 small-molecule antagonist in rheumatoid arthritis, with the capacity for disease modification.
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关键词
arthritis,inflammation,αlβ2,joint,small-molecule
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