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Fundamental research by Wayne State University is paving the way for development of first vaccine for heart diseases.

Researchers at Wayne State University have made a fundamental discovery and, in subsequent collaboration with scientists at La Jolla Institute for Allergy and Immunology (LIAI), are one step closer to the goal of developing the world’s first T-cell peptide-based vaccine for heart disease, the number one killer in the nation.

Atherosclerosis is a chronic inflammatory disease of the arterial walls, which thicken due to accumulation of fatty materials such as cholesterols and triglycerides. Blocking of arteries supplying blood to the heart is the underlying cause of many heart diseases.  Nearly 600,000 Americans die of heart disease every year. Although cholesterol is believed to be a major factor in creating the plaque that leads to heart disease, immune inflammation is another important contributor in arterial plaque buildup. The goal of the vaccine is to reduce immune-based inflammation in the arteries, leading to decreased plaque buildup.

The scientists first published their findings in the December 2013 issue of Frontiers in Immunology.  These experiments show proof of concept for the development of an autoantigen-specific vaccine for reducing the amount of atherosclerotic plaques in mice. If successful, the vaccine could aid in preventing heart disease and stop or reduce disease progression. In addition to heart disease, the vaccine could target strokes, which are also a product of plaque buildup in arteries.

The current study is the the first to demonstrate that two T cell epitopes of the autoantigen apoB100 are deeply involved in the development of the disease.  The novel discovery is published in the Journal of Immunology and Clinical Research.

ApoB100 is an apolipoprotein of the LDL (low-density lipoprotein) particle which is the notorious ‘bad cholesterol’ that contributes to the formation of plaques in the vessel wall.  Although T cells of the immune system are known to participate in the development of heart disease, by what and how these T cells are directed to act have not been elucidated. The lack of this knowledge has greatly hampered the development of immune peptide-based therapeutics to control the disease.  With the discovery of the disease-causing T cell epitopes, we can now manipulate the activities of the T cells responding to these epitopes to control the disease.

Since immune T cells are normally activated by a short sequence (called an epitope), and not by the whole molecule of an antigen, the team conceptualized that finding the apoB100 epitopes capable of stimulating the disease causing (atherogenic) T cells is a prerequisite for understanding how these T cells are involved in heart disease development and for finding ways to control their adverse effects.

Based on this idea, they identified two short sequences (3501–3515 and 978–992) of ApoB100 (ApoB3501-3515 and ApoB978-992, also designated peptides P3 and P6, respectively) that were able to direct specific T cells to proliferate as well as to cause worsening atherosclerosis. This discovery is significant because it identifies the target T cells and makes it possible to manipulate this population of pathologic T cells away from their harmful activities.

Source:  Wayne State University

Cardiomyocyte transfected with GFP and immunostained to show location of PDZ-ZM alpha-actinin.  Credit:  A.J.Wilson/Jenny Fordham/Pauline Bennett shortlisted for British Heart Foundation 'Reflections of Research' prize in 2007.
Cardiomyocyte transfected with GFP and immunostained to show location of PDZ-ZM alpha-actinin. Credit: A.J.Wilson/Jenny Fordham/Pauline Bennett
shortlisted for British Heart Foundation ‘Reflections of Research’ prize in 2007.

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