The role of T cell response to antigenic ApoB-100 peptides in vaccination strategies against atherosclerosis

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Atherosclerosis is a chronic inflammatory disease of the vessel wall. Its clinical complications, such as coronary heart disease, myocardial infarction, and stroke represent the leading cause of mortality worldwide. Despite considerable progress in the characterization of underlying inflammatory mechanism, such as the exact description of immune cell infiltration, no anti-inflammatory strategy could be translated into a clinically available therapy yet. From an immunological view, the inflammatory response represents the endpoint of many cellular and molecular interactions in the atherosclerotic plaque. A solid body of evidence implicates specific antigen recognition by T cells in the initiation of the inflammatory response. It was proposed that low-density lipoproteins (LDL) and their main protein components, such as Apolipoprotein (Apo) B-100, represent such auto-antigens. In line with the concept of an autoimmune response in atherosclerosis, vaccination approaches against some auto-antigens have been validated in some animal pilot studies, but neither cellular or molecular properties, mechanisms or consequences were clarified. In particular, some intriguing questions have not been answered: Is atheroprotection after immunization with modified lipids and antigenic peptides caused by a primary induction of a protective T cell subset or secondary by generation of protective auto-antibodies against antigenic peptides. Also, an antigen-specific therapy is not yet available in clinical practice. Recent innovation at the host institution, such as the identification of the exact antigen sequences of mouse ApoB-100 that confer atheroprotection in mice and the novel possibility to detect single antigenic T cells gave rise to the applicants working plan. In particular, the working plan was designed to clarify whether immunization with mouse ApoB-100 peptides modulates cytokine and differentiation profiles of CD4+ T cells into distinct TH-effector lineages and to describe how immunization regulates T-helper cell effector function in vitro and in vivo. Moreover, the exact functional role of tolerogenic dendritic cells and T-regulatory cells in conferring atheroprotection and the role of auto-antibodies against antigenic peptides will be addressed. Several genetic knock-out and transgenic animal models, adoptive transfer experiments and a novel live cell imaging approach to detect antigenic T cells ex vivo and in vivo will be employed. The indicated working plan will provide novel functional insight into mechanisms and consequences of vaccination against Apo B-100. The requested working plan is required for the ultimate goal of translating vaccination strategies into clinical practice.