Authors: Nishiyama, T.; Mishima, K.¹; Obara, K.¹; Inoue, H.¹; Doi, T.²; Kondo, S.²; Saka, M.²; Tabunoki, Y.²; Hattori, Y.²; Kodama, T.³; Tsubota, K.⁴; Saito, I.

Source: Clinical & Experimental Immunology, Volume 149, Number 3, September 2007 , pp. 586-595(10)

Publisher: Wiley-Blackwell

Abstract:

Summary

Regulation of the adhesion of mononuclear cells to endothelial cells is considered to be a critical step for the treatment of inflammatory diseases, including autoimmune diseases. K-13182 was identified as a novel inhibitor for these adhesions. K-13182 inhibited the expression of vascular cell adhesion molecule-1 (VCAM-1, CD106) on human umbilical vein endothelial cells (HUVECs) and on mouse vascular endothelial cell line (MAECs) induced by tumour necrosis factor (TNF)-α. K-13182 also inhibited the adhesion of mononuclear cells to these HUVECs and MAECs, indicating that K-13182 suppressed these adhesions mediated by cellular adhesion molecules including VCAM-1. To evaluate the therapeutic effect in autoimmune disease model mice, K-13182 was orally administered to non-obese diabetic (NOD) mice as Sjögren's syndrome (SS) model mice. Severe destructive inflammatory lesions were observed in the lacrimal glands of vehicle-treated control mice; however, 8-week administration of K-13182 inhibited the mononuclear cell infiltration into the inflammatory lesions of the lacrimal glands. In K-13182-treated mice, the decrease in tear secretion was also prevented compared to the control mice. In addition, the apoptosis and the expression of FasL (CD178), perforin, and granzyme A was suppressed in the lacrimal glands of K-13182-treated mice. Therefore, K-13182 demonstrated the possibility of therapeutic efficacy for the inflammatory region of autoimmune disease model mice. These data reveal that VCAM-1 is a promising target molecule for the treatment of autoimmune diseases as a therapeutic strategy and that K-13182 has the potential as a new anti-inflammatory drug for SS.

Keywords: autoimmune disease; endothelial cells; lacrimal gland; NOD mouse; VCAM-1

Document Type: Research article

DOI: http://dx.doi.org/10.1111/j.1365-2249.2007.03448.x

Affiliations: 1: Department of Pathology, Tsurumi University School of Dental Medicine, Yokohama, Japan, 2: Tokyo New Drug Research Laboratories II, Pharmaceutical Division, Kowa Co. Ltd, Tokyo, Japan, 3: Laboratory for Systems Biology and Medicine, Research Center for Advanced Science and Technology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan, and 4: Department of Ophthalmology, School of Medicine, Keio University, Tokyo, Japan

Publication date: 2007-09-01

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• In this Subject: Microbiology ,  Allergy & Immunology
• By this author: Nishiyama, T. ;  Mishima, K. ;  Obara, K. ;  Inoue, H. ;  Doi, T. ;  Kondo, S. ;  Saka, M. ;  Tabunoki, Y. ;  Hattori, Y. ;  Kodama, T. ;  Tsubota, K. ;  Saito, I.

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