A VLP‐based vaccine against interleukin‐1α protects mice from atherosclerosis

Abstract

Interleukin (IL)-1α is a potent proinflammatory cytokine that has been implicated in the development of atherosclerosis. We investigated whether a vaccine inducing IL-1α neutralizing antibodies could interfere with disease progression in a murine model of atherosclerosis. We immunized Apolipoprothin E (ApoE)-deficient mice with a vaccine (IL-1α-C-Qβ) consisting of full-length, native IL-1α chemically conjugated to virus-like particles derived from the bacteriophage Qβ. ApoE −/− mice were administered six injections of IL-1α-C-Qβ or nonconjugated Qβ over a period of 160 days while being maintained on a western diet. Atherosclerosis was measured in the descending aorta and in crosssections at the aortic root. Macrophage infiltration in the aorta was measured using CD68. Expression levels of VCAM-1, ICAM-1, and MCP-1 were quantified by RT-PCR. Immunization against IL-1α reduced plaque progression in the descending aorta by 50% and at the aortic root by 37%. Macrophage infiltration in the aorta was reduced by 22%. Inflammation was also reduced in the adventitia, with a decrease of 54% in peri-aortic infiltrate score and reduced expression levels of VCAM-1 and ICAM-1. Active immunization targeting IL-1α reduced both the inflammatory reaction in the plaque as well as plaque progression. In summary, vaccination against IL-1α protected ApoE −/− mice against disease, suggesting that this may be a potential treatment option for atherosclerosis. Keywords: Antibodies r Atherosclerosis r Macrophages r Vaccination IntroductionAtherosclerosis is a disease of the vasculature, causing thickening of the arterial wall, vascular remodeling, obstruction of the vessel lumen, and abnormal blood flow, and eventually diminished inflammatory reaction developing into the classical atherosclerotic plaque through macrophage and lymphocyte activation, and activation of the endothelium. This process further fosters oxidation of lipoproteins and increases inflammatory cell recruitment [2,3]. IL-1 is a potent proinflammatory cytokine with pleiotropic functions [4,5]. There are two subtypes, interleukin-1α (IL-1α) and interleukin-1β (IL-1β). Both proteins lack a signal peptide, and are first synthesized as precursor proteins [4]. The precursor form of IL-1α is biologically active, while the corresponding pro-IL-1β is not. IL-1β is processed into its mature form by caspase-1 and secreted upon inflammatory stimuli, in particular upon activation of the inflammasome [6]. IL-1α is predominantly found in its precursor form in the cytosol, or is membrane-bound [7]. Intracellular IL-1α has been reported to migrate into the nucleus, where it is thought to act as a transcriptional regulator. The prosequence can be cleaved by calpain, a membrane-associated protease, releasing mature IL-1α in the extracellular space [8]. IL-1α can, however, also be released into the extracellular space during apoptotic or necrotic processes. Interestingly, although IL-1α is not a substrate of caspase-1, the presence of the active enzyme is nevertheless required for release ...

Virus-like particle vaccines: immunology and formulation for clinical translation

“…A diverse range of applications for this type of modification have been investigated prophylactically and therapeutically for various conditions, including protection against infection from other organisms [47], autoimmune inflammatory disease [48], and as an antitumor immunotherapy [46,49,50]. Chimeric VLP have been investigated as a potential therapy for conditions not usually associated with vaccination, such as atherosclerosis [51], type II diabetes mellitus [52], and nicotine addiction [53]. Some of these VLP vaccines utilize chemical conjugation for incorporation of antigenic sequences as opposed to recombinant insertion.…”

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“…The same bacteriophage VLP technology has been used for vaccination against IL1β and IL1α [61]. It has been demonstrated that the IL1α active immunotherapy had the capacity to limit the development of atherosclerosis in mouse models [62]. Preclinical work demonstrated the efficacy of an anti-IL1β vaccine in mice [63] using a mutant IL1β protein with 10,000-fold lower bioactivity than native IL1β covalently linked to the Qβ bacteriophage.…”

Vaccine against arteriosclerosis: an update

“…Immunization with full-length, native IL-1α chemically conjugated to virus-like particles reduced inflammatory response in the plaques and atherosclerosis progression in aorta and aortic root. 64 …”