Fundamental research is paving the way for development of first vaccine for heart disease

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.

17 july 2014--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 arterialplaque buildup. The goal of the vaccine is to reduce immune-based inflammation in the arteries, leading to decreased plaque buildup.

The scientists published their findings in the December 2013 issue of Frontiers in Immunology, entitled "Atheroprotective vaccination with MHC-II restricted peptides from ApoB-100." 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 published work, performed in the laboratory of Klaus Ley, M.D., a prominent vascular biologist of LIAI, was based on the fundamental discovery made by Harley Tse, Ph.D., professor of immunology and microbiology in Wayne State's School of Medicine, and professor in Wayne State's Cardiovascular Research Institute, and Michael Shaw, Ph.D., adjunct assistant professor of immunology and microbiology at Wayne State. Shaw and Tse are the first to demonstrate that two T cell epitopes of the autoantigen apoB100 are deeply involved in the development of the disease. Their novel discovery is reported in the article, "Identification of two Immunogenic T cell Epitopes of ApoB-100 and their Autoimmune Implications," published in the April – June 2014 issue (volume 2) of 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," said Tse. "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, Shaw and Tse 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.

The subsequent collaboration with Ley's laboratory bears the first fruits of this effort.

Provided by Wayne State University

Research toward world's first vaccine for heart disease advanced

Research toward the world's first vaccine for heart disease continues to advance at the La Jolla Institute for Allergy and Immunology, with researchers demonstrating significant arterial plaque reduction in concept testing in mice.

18 jun 2014--Ley, M.D., a pioneer in vascular immunology, is leading the vaccine effort, which seeks to reduce plaque buildup in the arteries by targeting inflammation. In his latest finding, published recently in the journal Frontiers in Immunology, Ley used two mouse peptides, identified by Harley Tse, Ph.D., of Wayne State University, which he incorporated into testing the vaccine approach. In the study, vaccinated mice had about 40 percent less arterial plaque than mice that didn't receive the vaccine.

"Heart disease remains our nation's number one killer," says Mitchell Kronenberg, Ph.D., La Jolla Institute president &chief scientific officer. "We are excited by Dr. Ley's studies, which show promise for creating a vaccine that may one day reduce the incidence of this terrible illness." If successful, the vaccine could be given to aid in preventing heart disease and also to stop or reduce disease progression. In addition to heart disease, the vaccine could target strokes, which are also fueled by plaque buildup in the arteries.

The research drew praise from several cardiology experts. Stanley Hazen, M.D., Ph.D., section head of Preventive Cardiology at the Cleveland Clinic, one of the nation's top cardiology hospitals, called the research "elegant and tremendously exciting."

"This lays the groundwork for someday being able to prevent or even eradicate heart disease by giving a vaccine. Truly a remarkably important advance," says Hazen, also chairman of the Department of Cellular & Molecular Medicine.

Eric Topol, M.D., chief academic officer of Scripps Health and professor of genomics at The Scripps Research Institute, stressed the importance of Ley's work. "If successful, the potential development of a vaccine to prevent atherosclerosis would be a monumental advance in medicine," says Topol.

About 600,000 Americans die of heart disease every year, amounting to 1 in every 4 U.S. deaths. Most people know that cholesterol is a major factor in creating artery-clogging plaque leading to heart disease. However, many people may not be aware that inflammation is also a very important contributor to arterial plaque buildup. "Many research studies over the last 15 years have demonstrated inflammation's critical role in heart disease," says Ley. "By creating a vaccine to reduce inflammation in the arteries, we hope to significantly lessen the accompanying plaque buildup."

Ley's study was published December 27th in a paper "Atheroprotective vaccination with MHC-II restricted peptides from ApoB-100" in Frontiers in Immunology

Ley says the vaccine type he is exploring is different than those people get for the flu and other infections. "A flu vaccine's purpose is to teach your immune system to launch an attack if it encounters the virus," he says. "Our vaccine works more like the desensitization process used in allergy shots. Allergy shots are designed to teach the individual's immune system to tolerate the allergen. Our vaccine would work on the same principle—only in this case we'd be teaching the immune system to tolerate certain molecules of our own bodies that it mistakenly attacks, which causes inflammation."

In an earlier study, published August 13, 2012 in the Journal of Clinical Investigation, Ley identified that a specific type of immune cells (CD4 T cells) orchestrate the inflammatory attack on the artery wall by receiving antigen-specific signals from other inflammatory cells in the vessel wall. Further, he discovered that these immune cells behave as if they have previously seen the antigen that causes them to launch the attack. An antigen is a peptide derived from a virus, bacteria or, in the case of autoimmune diseases, one of our own proteins that the immune system mistakenly views as foreign and attacks.

Ley says that the discovery was particularly exciting since it meant the immune cells had 'memory' of the molecule brought forth by the antigen-presenting cells. "Immune memory is the underlying basis of successful vaccines," he explains. "This meant that conceptually it was possible to consider the development of a vaccine for heart disease."

Ley collaborated with fellow La Jolla Institute scientist Alessandro Sette, Ph.D. and Dr. Tse of Wayne State University in Michigan, to identify the specific peptides, which prompt the arterial attack in mice – the byproduct of which is inflammation. The mouse peptides were used in the test vaccine to teach the body, through gradual exposure, to tolerate rather than attack those proteins.

In parallel with that research Ley has worked with Sette, who is an internationally recognized vaccine biologist, to identify more candidate peptides with the goal of eventually creating a heart disease vaccine for people. "The next step is to test promising candidate peptides in specially engineered mice with an immune system more similar to humans," he says. If successful, the vaccine could begin human clinical trials in as little as three years, Ley adds.

The vaccine effort reflects the power of bringing top immunologists together in one institution, Ley notes. "It just shows what can happen when you have an institute like ours dedicated to immunology," says Ley. "Sette is a world renowned expert on vaccines and I have specialized knowledge in cardiovascular immunology. It's the combination of our two areas of expertise that is enabling this vaccine initiative to proceed. I don't think this could have happened anywhere else."