Cellular immune responses to low density lipoprotein in atherosclerosis

Abstract

Atherosclerosis is an inflammatory disease of the medium and large sized arterial vessels. Low density lipoprotein (LDL) particles carrying cholesterol are trapped within the arterial intima and elicit both innate as well as adaptive immune responses. T cells are present in the atherosclerotic plaque and cellular immunity plays an important role in lesion development. Mouse models of atherosclerosis are efficient means of unraveling the inflammatory process in the intima. The studies in this thesis have used some of these models to investigate the impact of the adaptive immunity on atherosclerosis and how antigen specific immunity can be explored to create new therapeutic opportunities.

Dendritic cells (DC) are potent inducers of T cells. To explore the effect of DC on atherosclerosis, in the context of an atherosclerosis-related antigen, we injected hypercholesterolemic Apoe-/- mice with malondialdehyde (MDA)-LDL pulsed DC. This cell transfer increased local inflammation in the vessel wall and accelerated plaque development. Importantly, the treatment also generated adaptive immune responses specific for components of LDL. This study suggests that DC can be used to influence atherogenic immunity.

The use of the hypercholesterolemic huB100tg x Ldlr-/- mouse model permitted us to study human LDL-derived epitopes to dissect the cellular autoimmune response in atherosclerosis. We demonstrated that CD4+ T cells, expressing T cell receptors (TCRs) with the variable beta domain TRBV31, recognize apolipoprotein B100 (ApoB100) of LDL and are needed for the development of advanced atherosclerosis. This illustrates the importance of ApoB100-specific T cell immunity in the atherogenic process.

Furthermore, we employed a strategy for immunoprotection of atherosclerosis by nasally administrating an ApoB100-derived peptide fused to the B-subunit of cholera toxin. This treatment targeted the mucosal immunity which led to an induction of antigen-specific regulatory T cells and significantly reduced atherosclerosis in Apoe-/- mice.

Finally, to make use of DC as a treatment modality for atherosclerotic disease, we injected huB100tg x Ldlr-/- mice with DC that had been made tolerogenic by treatment with IL-10 and ApoB100. This led to a very significant reduction of atherosclerotic lesions in the aorta with decreased CD4+ T cell infiltrates and dampened systemic inflammation. The tolerogenic DC therapy diminished the autoreactive T cell response to ApoB100, showing the relevance of antigen-specific immunity in atherosclerosis and treatments thereof. In conclusion, we have studied the adaptive immunity to ApoB100 of LDL in mouse models. This has led to the identification of novel therapeutic targets for cardiovascular disease. We found that pro-atherosclerotic T cells can recognize ApoB100 and that DC can present epitopes of LDL and activate pro-inflammatory T cells. When manipulating DC to induce T cell tolerance to ApoB100, immunoprotection is established with reduced atherosclerosis as a consequence. Finally, by using derivatives of ApoB100 for mucosal vaccination we could also target atherosclerosis development.