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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2004;24:1409.)
© 2004 American Heart Association, Inc.

Vascular Biology

Attenuation of Graft Arterial Disease by Manipulation of the LIGHT Pathway

Hisanori Kosuge; Jun-ichi Suzuki; Tsunekazu Kakuta; Go Haraguchi; Noritaka Koga; Hideki Futamatsu; Ryo Gotoh; Manabu Inobe; Mitsuaki Isobe; Toshimitsu Uede

From the Department of Cardiovascular Medicine (H.K., J.S., T.K., G.H., N.K., H.F., R.G., M. Isobe), Tokyo Medical and Dental University, Yushima, Bunkyo-ku, Tokyo, Japan; and the Division of Molecular Immunology (M. Inobe., T.U.), Institute for Genetic Medicine, Hokkaido University, Kita-ku, Sapporo, Japan.

Correspondence to Mitsuaki Isobe, Department of Cardiovascular Medicine, Tokyo Medical and Dental University, 1-5-45, Yushima, Bunkyo-ku, Tokyo 113-8519, Japan. E-mail isobemi.cvm{at}tmd.ac.jp

Objective— The tumor necrosis factor (TNF) superfamily member LIGHT, which binds herpes virus entry mediator (HVEM) and lymphotoxin ß receptor (LTßR), plays important roles in regulating the immune response. To clarify the mechanism underlying graft arterial disease (GAD), we investigated the role of the LIGHT pathway in the progression of GAD.

Methods and Results— Hearts from Bm12 mice were transplanted into C57BL/6 (B/6) mice (class II mismatch). Recipients were injected intraperitoneally with HVEMIg (100 µg per treatment) every 7 days for 8 weeks. Treatment with HVEMIg significantly attenuated GAD (luminal occlusion=16.5±7.7% versus control allograft=62.6±12.1%, P<0.05), and significantly decreased intragraft IL-4, IL-6, and interferon- (IFN-) mRNA expression compared with controls. LTßR was expressed in smooth muscle cells (SMCs) with or without cytokine stimulation, whereas HVEM was detected in SMCs stimulated by IFN-. Coculture of SMCs with T cells after transplantation induced SMC proliferation, and addition of HVEMIg resulted in inhibition of SMC proliferation.

Conclusions— These results indicate that the LIGHT pathway plays important roles in the regulation not only of T-cell activation but also of SMC proliferation. Blockade of the LIGHT pathway is a promising avenue for the prevention of GAD.

The role of the LIGHT pathway in the progression of graft arterial disease (GAD) is not yet evaluated. We demonstrate that blockade of the LIGHT pathway plays important roles in the regulation not only of T cell activation but also of smooth muscle cell proliferation, resulting in prevention of GAD.

Key Words: arteriosclerosis • transplantation • costimulatory molecules • immune system • smooth muscle cells

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