Abstract 1353: DNA vaccination Against IL-17 Attenuates Atherosclerosis in LDL Receptor Deficient Mice
Interleukin 17 (IL-17) is a pro-inflammatory cytokine that has been linked to a number of autoimmune diseases. IL-17 is produced by recently discovered IL-17 memory/helper T (Th-17) cells and is primarily induced by IL-23. IL-17 exhibits pleiotropic effects on atheroma-associated cell types and induces secretion of pro-inflammatory cytokines and matrix metalloproteinases, which may contribute to atherosclerotic lesion formation. Here we describe the effect of IL-17 blockade on atherosclerosis by vaccination against IL-17. LDL receptor deficient (LDLr−/−) mice were vaccinated against IL-17 using a plasmid encoding IL-17 and the dominant T helper cell epitope HEL (IL-17-HEL), prior to induction of atherosclerosis by feeding a Western type diet (0.25% cholesterol). Vaccination was performed by intramuscular (i.m.) injection of IL-17-HEL or by oral administration of attenuated Salmonella typhimurium (S. typhi) transformed with IL-17-HEL. The efficiency of IL-17 vaccination was determined in vivo. IL-17-HEL vaccination blocked the induction of IL-6 after an intravenous injection of recombinant IL-17. IL-6 serum levels in vaccinated mice were significantly reduced by 31% (p<0.05). Subsequently, we determined the effect of IL-17 vaccination on atherosclerotic lesion formation. DNA vaccination via i.m. injection of IL-17-HEL (N=9) resulted in a decrease in plaque size of 90% compared to injection with an empty plasmid (N=8)(5654 μm2 vs. 57702 μm2, p<0.01). Oral vaccination with S. typhi transformed with IL-17-HEL plasmid (N=8) attenuates atherosclerosis with 75% compared to vaccination with an empty plasmid (N=7)(13039 μm2 vs. 52888 μm2, p<0.05). Oral vaccination of LDLr−/− mice with S. typhi transformed with an IL-17 plasmid without the HEL epitope (N=9) did not affect atherosclerosis. We conclude that disruption of the IL-17 pathway by DNA vaccination is dependent on the presence of the HEL epitope in the vaccine. Successful vaccination with IL-17-HEL impaired IL-17 dependent IL-6 production. In addition successful DNA vaccination resulted in a vast decrease in atherosclerotic lesion formation and it may be speculated that IL-17, produced by the newly identified Th-17 cells, can be a major target for vaccination against atherosclerosis.