What if we could screen for heart disease earlier and improve patient outcomes?
FUNDED: JANUARY 2021
FUNDED BY: The generosity of LJI Board Director (’16-’22) Dave Rickey and the Rickey Family.
What was the goal of your SPARK project?
A T cell response is not a random event, but is directed towards specific molecules known as “antigens.” Normally, T cells respond only to foreign antigens, such as markers on bacteria and viruses. But in the case of heart disease, some rogue T cells recognize self-antigens, i.e., molecules that are present in our own bodies. In mouse models, researchers have shown that apolipoprotein B, the protein that forms the backbone of low-density lipoprotein (LDL), is a major inducer of heart disease-related harmful immune responses.
Therefore, I focused my attention on this protein and began to set up experimental strategies to examine whether human T cells similarly respond to this self-antigen.
My goal was to optimize and validate re-stimulation-based protocols that can detect and characterize autoimmune T cell responses to human apolipoprotein B. My goal was to shed light on heart disease by developing assays that can detect, as well as reveal, the biological identities of the harmful T cells.
Did you face any challenges?
Overall, LJI managed the pandemic situation extremely well and the net negative impact on my research workflow was minimal. However, the patient samples that I was expecting to receive through University of California, San Diego (UC San Diego) Health could not be acquired until late 2021, due to COVID-19-related restrictions. Despite this, I was able to complete my SPARK project by managing to receive patient samples through our collaborators at University of Virginia (UVA) Health.
SPARK project results:
I optimized my immunological assays and achieved high levels of sensitivity that allowed detection of rogue T cells in the blood of study subjects. These T cells exhibited an inflammatory phenotype, concordant with their postulated role in triggering chronic inflammation that
characterizes the long latent phase of heart disease. I discovered that six specific regions, known as “epitopes,” in the human apolipoprotein B self-antigen have predominant roles in inducing the rogue T cells.
Next, I wanted to explore the potential of my immunological assays as a screening tool. To do this, I adopted two different strategies. First, I collected blood samples from donors from different age groups (range 20 – 66 years). One part of the sample was sent to clinical labs at UC San Diego to measure lipid risk factors, such as triglyceride, total cholesterol, LDL-cholesterol, etc. The other part of the sample was used to run my immunological tests. None of these donors had a known condition of heart disease.
I found that donors who had elevated levels of lipid risk factors also showed increased responses in my assays. Such heightened immunological responses were detectable even in donors who were in their 20s and 30s.
Second, I obtained blood samples from patients undergoing coronary angiography at the UVA. They were divided into low and high severity groups based on their heart disease burden (standard angiographic scores). Rogue T cell responses were significantly higher in patients who were angiographically determined to have high cardiovascular disease burden.
In the end, I showed that my assays can detect heart disease-related inflammatory T cell responses in young and middle-aged people who have abnormal levels of blood lipids and cholesterol. A strong correlation exists between my assay scores and angiographic scores of heart disease. This signifies the tremendous potential of this workflow in evaluating early signs of the disease.
My work was recently published in Circulation Research, one of the top journals related to heart disease. This work also led to a patent application covering TCR-based cardiovascular diagnostics and therapeutics which was submitted in June 2022.
What’s next for this project?
We have acquired more samples from patients recruited through Scripps Health, UC San Diego, and the UVA. Our plan is to explore whether similar associations between APOB-specific T cell responses, cardiovascular lipid risks and disease severity exist in multiple cohorts. In-depth statistical analyses will be performed to determine whether my assay readouts can be developed as a biomarker. I will also undertake transcriptomic profiling of these APOB-specific T cells to learn more about their functional states and to identify any potential modifiable targets for intervention. Together these studies will facilitate immunological assessment of cardiovascular risks and will shed light into the pathophysiological nature of autoimmune-related cardiovascular disease.
What’s next for Payel?
While my P.I., Klaus Ley, Ph.D., has accepted a new position at the Medical College of Georgia, I will continue to work with Dr. Ley and complete my post doc at LJI through the end of 2023. I would like to continue in academia and wish to one day open my own lab. I intend to continue to study heart disease, but would also like to broaden my horizons by also looking at related disorders and understanding inter-disease relationships.
“My experience as a SPARK finalist has inspired me to understand the true essence of my research. Winning this award will further instill confidence that my scientific ideas have the potential to make a difference and save lives. That kind of motivation is far stronger than any scientific accomplishment.”