Case 2020-386
UCLA researchers from the Department of Medicine have created a novel multi-omics approach to investigating immune health.
BACKGROUND
All living organisms have developed a highly conserved and regulated response to cope with a broad spectrum of stressful stimuli, including strenuous exercise. Exercise exerts beneficial physiological effects and has the potential to delay, halt, or even reverse declines in immune function. During exercise, cell-free DNA (cf DNA), including nuclear DNA and mitochondrial DNA (cf-mtDNA), are produced by cellular injury and interact with peripheral blood mononuclear cells (PBMC). This leads to alterations in the PBMC gene expression profile and the release of pro- and anti-inflammatory cytokine mediators. During intense bouts of physical activity in healthy individuals, production and removal of cf-mtDNA from circulating blood act as an anti-inflammatory mechanism. Therefore, regular exercise provides health benefits by reducing systemic inflammation.
In contrast to healthy individuals, patients with chronic disease conditions like heart failure (HF), have an adrenergic system that is permanently activated: exhibiting a maladaptive pro-inflammatory equilibrium. This maladaptive pro-inflammatory response, leads to chronic disease patient populations with poor exercise tolerance. While mechanistic links have been postulated between inflammation, muscle weakness, frailty, catabolic/anabolic imbalance, aberrant chronic activation of immunity, and chronic fatigue syndrome, these links have not been clinically translated to increasing exercise tolerance, showing poor utility. One potentially powerful approach to the identification of clinically relevant factors to increase exercise tolerance in individuals with chronic disease, is the use of multi-omics. Cardiopulmonary exercise (CPX) testing, which is routinely performed in clinical settings as a standard assessment of cardiorespiratory fitness, may be combined with techniques that survey the immune health of individuals to holistically build an immunological patient profile. The outcome of such an approach, could hold enormous implications in the prediction and treatment recommendations of patients.
INNOVATION
UCLA researchers propose to identify a unique multi-omics model that can serve as a tool for investigating the biology of immune health concerning prognosis, monitoring, and response to therapy in a given person. They have developed the concept of a novel multi-omics model called MyExerciseLeukoMAP that can serve as a tool for investigating a patient’s immune health. This approach profiles cell-free DNA, mRNA, peripheral blood subpopulations, and cytokine levels of blood samples before, after, and during a patient undergoes a cardiopulmonary exercise to build a complete immunological patient profile. MyExerciseLeukoMAP can also be used to uncover the connection between cell-free DNA and immunological health. MyExerciseLeukoMAP allows for personalized outcome prediction and treatment recommendations for patients in high-risk groups.
POTENTIAL APPLICATIONS
• Determine patient’s immune health
• Screen patients for positive outcomes for advanced heart failure therapies
• Screen patients for positive outcomes from other high-risk surgeries and treatments
ADVANTAGES
• Quantitative, multi-omic measurement of immune health
• Personalized approach to patient treatment
• Analyzes patient blood on the DNA, RNA, and protein levels
DEVELOPMENT-TO-DATE
In a proof-of-concept study, 4 healthy volunteers and 16 patients with chronic heart failure were evaluated. Clinical data were collected, and all participants underwent cardiopulmonary exercise testing where blood samples were drawn before, during, and after exercise. The blood samples underwent DNA and RNA sequencing, flow cytometry, and cytokine analysis.
RELATED MATERIALS
Bondar G, Cadeiras M, Wisniewski N, Maque J, Chittoor J, Chang E, Bakir M, Starling C, Shahzad K, Ping P, Reed E, Deng M. Comparison of whole blood and peripheral blood mononuclear cell gene expression for evaluation of the perioperative inflammatory response in patients with advanced heart failure. PloS one. 2014 Dec 17;9(12):e115097.
Wisniewski N, Bondar G, Rau C, Chittoor J, Chang E, Esmaeili A, Cadeiras M, Deng M. Integrative model of leukocyte genomics and organ dysfunction in heart failure patients requiring mechanical circulatory support: a prospective observational study. BMC medical genomics. 2017 Dec;10(1):52.
Bondar G, Togashi R, Cadeiras M, Schaenman J, Cheng RK, Masukawa L, Hai J, Bao T, Chu D, Chang E, Bakir M, Kupiec-Weglinski S, Groysberg V, Grogan T, Meltzer J, Kwon M, Rossetti M, Elashoff D, Reed E, Ping P, Deng M. Association between preoperative peripheral blood mononuclear cell gene expression profiles, early postoperative organ function recovery potential and long-term survival in advanced heart failure patients undergoing mechanical circulatory support. PloS one. 2017 Dec 13;12(12):e0189420.
Deng MC. A peripheral blood transcriptome biomarker test to diagnose functional recovery potential in advanced heart failure. Biomarkers in medicine. 2018 May 8;12(6):619-35.