Interruption of the Tnfrsf4/Tnfsf4 (OX40/OX40L) pathway attenuates atherogenesis in low-density lipoprotein receptor-deficient mice.
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.


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.
van Wanrooij
Eva J A
EJ
Division of Biopharmaceutics, Leiden/Amsterdam Center for Drug Research, Gorlaeus Laboratories, Leiden University, P.O. Box 9502, 2300 RA Leiden, The Netherlands. e.van.wanrooij@chem.leidenuniv.nl
van Puijvelde
Gijs H M
GH
de Vos
Paula
P
Yagita
Hideo
H
van Berkel
Theo J C
TJ
Kuiper
Johan
J
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology / Q000517:prevention & control; D002339:Carotid Arteries / Q000378:metabolism / Q000473:pathology; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D007075:Immunoglobulin M / Q000378:metabolism; D015847:Interleukin-4 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D053278:OX40 Ligand / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism*; D053262:Receptors, OX40 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D018418:Th2 Cells / Q000187:drug effects / Q000502:physiology
D000911:Antibodies, Monoclonal; D007075:Immunoglobulin M; D053278:OX40 Ligand; D011973:Receptors, LDL; D053262:Receptors, OX40; C505717:Tnfrsf4 protein, mouse; D015847:Interleukin-4