“A better understanding of which cells are involved in promoting the inflammation of clogged arteries in patients with atherosclerosis may give us a target for a new drug to limit the damage following heart attacks.”
A new cellular target to prevent tissue damage following heart attack
FUNDED: JANUARY 2020
FUNDED BY: the generosity of The Rickey Family
Cardiovascular diseases, including heart attacks, are the leading cause of death worldwide. Heart attacks occur when a fatty plaque grows slowly over time inside the blood vessel, but then suddenly bursts, leading to clogged blood flow and cutting off vital oxygen supply. Although 90% of patients survive the initial clogging event, major tissue damage occurs in the following weeks that increases risk for secondary infarcts and complications. The same creeping process of lipid plaque accumulation that leads to an inflamed artery is at play in stroke and abdominal aortic aneurisms, just at different locations, and is collectively called atherosclerosis.
Years of fundamental research on animal model systems have shown that specific cells in the immune system, called natural killer T (NKT) cells, are a major contributor to the tissue damage that occurs after the first heart attack. With their unique ability to sense and respond to dietary fats, NKT cells accumulate and get activated in the atherosclerotic plaque, fueling inflammation. We have robust evidence from these models that places NKT cells at center stage in mediating the damage to the organ, and targeting NKT cells with drugs has already shown impressive reduction in lesion size and improved tissue health in mice.
However, to date, the results from these animal studies have not been translated to patients, presumably due to the technical challenge of detecting NKT cells and a lack of access to patient samples. We hypothesize that human NKT cells also become activated and greatly contribute to the inflammation following a patient´s heart attack. I will test this hypothesis through a new collaboration with Professor Ashok Handa at Oxford University, U.K., who will provide aortic tissue and matched blood samples from patients that underwent surgery to remove part of their aorta that contains a dangerous plaque. Using state of the art immunological and sequencing techniques, we will compare the levels of activation of NKT cells to determine whether NKT cell activation is associated with heart disease in humans. If successful, this work will demonstrate the relevance of NKT cell activation in humans, which is critical to lay the groundwork for clinical studies that test NKT cell depletion to limit tissue damage following a heart attack. Importantly, a drug that can deplete NKT cells in humans is available to us and currently tested by us in a different context.
Six-Month Project Update
My proposed project relies on access to clinical samples from patients that experienced a hypoxic inflammatory disease, like atherosclerosis. I had a planned collaboration with a colleague at Oxford University to collect patient samples, however, due to the pandemic, this collaboration was no longer a viable option. In response, I shifted focus to sickle cell disease, because I have better access to patient samples, and it still allows us to answer essentially the same question: Does lack of oxygen in the blood vessel cause the activation of natural killer T (NKT) cells? Like in atherosclerosis, lack of oxygen may be causing the NKT cell activation in the sickle cell patients. Thus far, I’ve set up a collaboration with the University of Wisconsin to get these patients’ blood samples. We’ve already received the first of these samples and I’m working with the flow cytometry core to characterize the patient NKT cells. Concurrently, we are awaiting IRB approval to recruit healthy blood donors to use as appropriate controls for sickle cell patients. While we wait, I’ve also set up an animal model of this disease which we can analyze in parallel to complement our findings. Once all samples are received, the analysis strategy remains the same: purify NKT cells from healthy patient samples and conduct single-cell sequencing to test if we find evidence for a contribution to inflammation by NKT cells. This will help us to understand how much NKT cells contribute to underlying mechanisms of inflammation.