This Article Full Text Full Text (PDF) Data Supplement All Versions of this Article: 27/1/204    most recent 01.ATV.0000251007.07648.81v1 Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by van Wanrooij, E. J.A Articles by Kuiper, J. Search for Related Content PubMed PubMed Citation Articles by van Wanrooij, E. J.A Articles by Kuiper, J. Pubmed/NCBI databases Gene GEO Profiles HomoloGene UniGene Substance via MeSH Related Collections Pathophysiology Gene expression Growth factors/cytokines

(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

This article has been cited by other articles:

				P. Libby, P. M. Ridker, G. K. Hansson, and for the Leducq Transatlantic Network on Atherothro Inflammation in Atherosclerosis: From Pathophysiology to Practice J. Am. Coll. Cardiol., December 1, 2009; 54(23): 2129 - 2138. [Abstract] [Full Text] [PDF]

				I. Gotsman, A. H. Sharpe, and A. H. Lichtman T-Cell Costimulation and Coinhibition in Atherosclerosis Circ. Res., November 21, 2008; 103(11): 1220 - 1231. [Abstract] [Full Text] [PDF]

				A. Malarstig, P. Eriksson, L. Rose, K. A. Diehl, A. Hamsten, P. M Ridker, and R. Y.L. Zee Genetic Variants of Tumor Necrosis Factor Superfamily, Member 4 (TNFSF4), and Risk of Incident Atherothrombosis and Venous Thromboembolism Clin. Chem., May 1, 2008; 54(5): 833 - 840. [Abstract] [Full Text] [PDF]