Abstract 253: Interruption of the TNFRSF4/TNFSF4 Ligand Pathway Attenuates Atherogenesis in LDL Receptor Deficient Mice
Atherosclerosis is a chronic (auto)-inflammatory disease in which T cell activation is an important factor. TNFRSF4 (CD134) and TNFSF4 (CD134L) are members of the TNF and TNF receptor family and the CD134/CD134L pathway is an important co-activator of T cells during immune responses, while activated CD134 positive T cells may enter the vessel wall via CD134L expressed by endothelial cells. Recently, CD134L was identified as the gene within the Ath1 QTL responsible for the atherosclerosis susceptibility of C57Bl6 mice. In the present study we assess the role of the CD134/ CD134L pathway in atherosclerosis and the effect of an CD134L blocking antibody on atherosclerosis. Analysis of the CD134 expression in the spleen of LDL receptor deficient (LDLr−/−) mice fed a Western type diet (0.25% cholesterol) showed that the CD134 mRNA levels were induced significantly 4.5-fold (p=0.03). This resulted in an 2.5 and 5-fold significant increase in CD134 expression on circulating CD4 and CD8 positive T cells as determined using FACS cytometry. Treatment of LDLr−/ − mice with an anti-CD134L antibody resulted in a 53% decrease in collar induced atherosclerotic lesion formation (p<0.01), without an effect on serum cholesterol levels. Anti-CD134L antibody treatment resulted in a significant 50% decrease in CD134 mRNA expression in the spleen as compared to control treated LDLr−/ − mice, indicating a reduction in splenic T cell activation upon blockade of the CD134/ CD134L interaction. We conclude that the induction of CD134 positive T cells during the course of atherosclerosis accelerates the process of atherosclerosis and interruption of the CD134/ CD134L pathway is a new target for the development of immunomodulatory drugs for the treatment of cardiovascular disease.