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.
