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Overview

The underlying cause of many heart attacks is atherosclerosis, defined as build-up of deposits, or plaques, of cholesterol, calcium, and other substances in arteries. Over time, plaques limit blood flow, and, if they obstruct a vessel like the coronary artery, can trigger a heart attack. Artery blockage in other organs is also hazardous and can damage kidney, the extremities (in the case of peripheral artery disease), or the brain. Plaque rupture also increases the chance of stroke or blood clots in the brain.

Most people are well-schooled in the knowledge that excess cholesterol is a major factor in creation of artery-clogging plaques. But recently investigators have realized that it is actually the inflammation emerging at sites of vessel tissue damage that encourages arterial plaque buildup in the first place, suggesting that dialing down inflammation might be as effective against arterial plaques as dietary or pharmaceutical interventions.

Our Approach

With that knowledge, LJI’s Klaus Ley, M.D., is working on vaccines that target inflammatory factors as a means to reduce atherosclerotic plaque formation. Using a mouse model of atherosclerosis, Ley inoculated animals with the vaccine and observed approximately 50% less plaque in their arteries compared to arteries from unvaccinated mice. Working in collaboration with LJI Alessandro Sette, he has now identified several peptides suitable for vaccinating humans and will test those in mice engineered to harbor a humanized immune system. Their current goal is to enter phase I clinical trials in 2 years. If successful, this achievement would constitute the worlds’ first vaccine for heart disease.

Atherosclerosis and Diabetes
Atherosclerosis and diabetes go hand in hand: type 1 and type 2 diabetes sufferers are four times more likely to die of heart attack than the general population. To understand why, LJI’s Catherine Hedrick, Ph.D., studies how elevated cholesterol contributes to atherosclerosis. To that end, she genetically engineered mice to lack a protein that transports cholesterol out of cells in order to analyze experimentally what happens when immune cells remain abnormally packed with cholesterol. She observed that the repertoire of immune cell subtypes differed between normal and engineered mice, and furthermore, that T cells of engineered mice fed a “western” (fatty) diet produced inordinately high levels of pro-inflammatory cytokines. This hints that cholesterol overload may prompt cells to overproduce inflammatory factors that foment plaque formation.

A fascinating corollary to this story has recently emerged. Hedrick observed when infused with tumor cells, the very same mice lacking the cholesterol transporter exhibited lower rates of bladder cancer and melanoma than did normal animals. Furthermore, their bloodstream showed an upsurge in the number of macrophages, immune cells capable of scavenging and thus carting off tumor cells. This finding suggests that high cellular cholesterol content could push immune cells like macrophages into tumor-fighting mode and presents a very intriguing paradox: namely that inflammation that is deadly in the context of atherosclerosis may be beneficial when it comes to cancer.

Research Projects

Sette
Athlerosclerosis

ATHEROSCLEROSIS Working in collaboration with LJI Professor Klaus Ley, the Sette Lab aims to help develop vaccines that target inflammatory

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Hedrick
Regulation of Treg Function in Cardiovascular Disease

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Hedrick
CD8 T Cell Functions in Atherosclerosis

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More research projects

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Labs

Jul 8, 2020
Ley Lab

Klaus Ley, M.D., and his team study inflammation in health and disease. The lab is focused on mechanisms by which immune cells reach sites of inflammation, as well as investigating atherosclerosis.

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Klaus Ley, M.D.
Professor
Center for Autoimmunity and Inflammation
Jul 8, 2020
Hedrick Lab

Catherine "Lynn" Hedrick, Ph.D., and her lab members study and target monocytes to aid in the prevention of cancer. The lab also investigates neutrophil heterogeneity in cancer and cardiovascular disease.

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Catherine Hedrick, Ph.D.
Professor
Center for Autoimmunity and Inflammation, Center for Cancer Immunotherapy