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

作者：Eva J.A. van Wanrooij, Gijs H.M. van Puijvelde, Paul de Vos, Hideo Yagita∥, Theo J.C. van Berkel, Johan Kuiper · 发表于：Arteriosclerosis Thrombosis and Vascular Biology · 年份：2006 · DOI：10.1161/01.atv.0000251007.07648.81 · 被引用次数：111 · 研究领域：Atherosclerosis and Cardiovascular Diseases、Neutrophil, Myeloperoxidase and Oxidative Mechanisms、T-cell and B-cell Immunology

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.