Published online by Nature Medicine May 12, 2003 -- Printed edition scheduled for June 2003

Vaccination Halts Progression of Atherosclerosis
In Animal Studies, UCSD Researchers Report

Researchers at the University of California, San Diego (UCSD) School of Medicine have shown in mice that a vaccine for pneumonia also triggers elements of the immune system to reduce atherosclerosis, the build-up of fatty deposits and chronic inflammation in blood vessels, which leads to heart attacks and stroke.

While pneumococcal vaccination is known to build the body's defenses against bacterial pneumonia, this is the first demonstration that a pneumococcal vaccine can also protect the host from a chronic inflammatory disease process such as atherosclerosis.

In a study published in the June 2003 issue of the journal Nature Medicine, the researchers demonstrate that vaccination with pneumococci microbes, and the resulting immune response triggered by the body, reduced the extent of atherosclerosis by 21 percent in laboratory mice that are used as a model for coronary disease.

A complex disease with multiple causes, atherosclerosis has traditionally been considered a disorder caused by excess levels of cholesterol in the body. More recently, scientists have identified the chronic inflammatory process of the disease, with recent studies suggesting that the body's natural immune responses might be able to modulate the progression of atherosclerosis.

The study's first author, Christoph J. Binder, M.D., Ph.D., a post-doctoral researcher in the lab of co-senior author Joseph Witztum, M.D., said "the test of pneumococcal vaccination grew from the team's study of immune responses against oxidized low-density lipoproteins (LDL), the 'bad' cholesterol that leads to plaque build-up in arteries."

For the past 20 years, the Witztum lab at UCSD, in collaboration with UCSD professor of medicine Daniel Steinberg, M.D., Ph.D., has pioneered the role of oxidized LDL as a major contributing factor for the development of atherosclerosis. In particular, the Witztum lab has been studying immunological response to oxidized LDL and its impact on development and modulation of atherosclerosis.

Once LDL becomes oxidized, it undergoes structural changes in such a way that it is recognized by the host's immune system. Macrophages, scavenger cells that have been drawn to the site, engulf the oxidized LDL and become "foam cells," the hallmark of atherosclerotic plaques.

In the current study, the scientists discovered that a chemical structure called phosphorylcholine on the surface of oxidized LDL was identical to a molecular site on S. pneumoniae, the major cause of bacterial pneumonia. In turn, a natural antibody, IgM, reacted with both pneumococcal bacteria and oxidized LDL by binding to that chemical structure. Based on these observations, the scientists tested vaccination with pneumococci in laboratory mice and determined that the resulting immune response arrested the progression of atherosclerosis.

"We've established that IgM antibodies specific for oxidized LDL have a protective role in atherosclerosis," said Witztum, a UCSD professor of medicine. "This provides insight into the biological role of these immune responses and is an important basis for the development of therapeutic interventions."

Co-senior author Gregg Silverman, M.D., UCSD professor of medicine, and his group have been studying the response of the immune system to bacterial infections for more than 10 years.  He noted that "researchers have used this same bacterial immunization for decades to study an antibody response important for defense from infection. No one previously suspected that there might be relevance to other types of diseases, especially a disease like atherosclerosis."

"Our next step will be to identify and better characterize the equivalent immune responses in humans, with the hope of eventually designing a vaccine specific to atherosclerosis," Witztum said.

The study was supported by the Specialized Center of Research in Molecular Medicine and Atherosclerosis at the National Institutes of Health.

Sohvi Hörkkö, M.D., Ph.D., University of Oulu, Finland, and Asheesh Dewan,M.D., UCSD Division of Endocrinology & Metabolism, were equal contributors to this study, as was co-senior author Wulf Palinski, M.D., UCSD professor of medicine. Additional authors were Mi-Kyung Chang, M.D., Emily P. Kieu, Carl S. Goodyear, Ph.D., UCSD Division of Rheumatology, Allergy and Immunology; and Peter S. Shaw, Ph.D., UCSD Division of Endocrinology & Metabolism.

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