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(Arteriosclerosis, Thrombosis, and Vascular Biology. 2007;27:204.)
© 2007 American Heart Association, Inc.

Atherosclerosis and Lipoproteins

Interruption of the Tnfrsf4/Tnfsf4 (OX40/OX40L) Pathway Attenuates Atherogenesis in Low-Density Lipoprotein Receptor-Deficient Mice

Eva J.A van Wanrooij; Gijs H.M van Puijvelde; Paula de Vos; Hideo Yagita; Theo J.C. van Berkel; Johan Kuiper

From the Division of Biopharmaceutics (E.J.A.v.W., G.H.M.v.P., P.d.V., T.J.C.v.B., J.K.), Leiden/Amsterdam Center for Drug Research, Gorlaeus Laboratories, Leiden, The Netherlands; and the Department of Immunology (H.Y.), Juntendo University School of Medicine, Bunkyo-ku, Tokyo, Japan.

Correspondence to Eva J.A. van Wanrooij, Division of Biopharmaceutics, Leiden/Amsterdam Center for Drug Research, Gorlaeus Laboratories, Leiden University, P.O. Box 9502, 2300 RA Leiden, The Netherlands. E-mail e.van.wanrooij{at}chem.leidenuniv.nl

Objective— Atherosclerosis is a chronic (auto-)inflammatory disease and T cell activation is an important factor in this process. Tnfrsf4 (OX40) and Tnfsf4 (OX40 ligand) are members of the tumor necrosis factor (TNF) and TNF receptor family and OX40/OX40L mediated signaling is important in co-activation of T cells and facilitates B-T cell interaction. In this study we assessed the role of the OX40/OX40L pathway in atherosclerosis and the effect of interruption of the OX40/OX40L pathway on lesion development.

Methods and Results— We treated low-density lipoprotein receptor-deficient (LDLr^–/–) mice with an anti-OX40L antibody which lead to a 53% decrease in atherosclerotic lesion formation. Treatment resulted in inhibition of Th2 mediated isotype switching by decreasing interleukin (IL)-4 secretion and subsequent low IgG1 serum levels against oxLDL, whereas protective anti-oxLDL specific IgM titers were increased in treated mice compared with control.

Conclusions— We conclude that blocking the OX-40/OX40L interaction reduced atherogenesis by inhibition of IL-4 mediated Th2 induced isotype switching and subsequent increased levels of anti-oxLDL IgM.

Tnfrsf4 (OX40) and Tnfsf4 (OX40 ligand) are members of the TNF and TNF receptor family and the OX40/OX40L pathway is an important co-activator of T cells. Anti-OX40 ligand antibody administration reduced atherogenesis by inhibiting IL-4 induced IgG1 isotype switching, and increased anti-oxLDL specific IgM serum levels.

Key Words: atherosclerosis • OX40 • OX40L • isotypeswitch • IgM

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