Researchers at Washington University School of Medicine in St. Louis have received a $6 million grant from the National Heart, Lung, and Blood Institute of the National Institutes of Health (NIH) to harness new knowledge about the immune system to developing innovative therapies for the heart. heart failure and prevention of organ rejection after heart transplantation.
The research will build on the work carried out by the principal investigator and the cardiologist Kory J. Lavine, MD, Ph.D., Associate Professor of Medicine. Lavine and her team identified important immune cells in the heart, called macrophages, that play key but divergent roles in damaging inflammation and beneficial healing. Whether specific macrophages are helpful or harmful depends on where the cells come from in the body. Macrophages involved in wound healing grow and reside in the heart, while harmful macrophages are recruited from the bone marrow during times of stress and injury. Finding ways to block harmful bone marrow cells and nurture those already healing in the heart could lead to new therapies for various types of heart failure and methods to protect a transplanted heart from rejection by the system. body’s immune system.
“We are excited about research in cardiovascular medicine that could open the door to reducing inflammation and promoting healing in the failing heart,” Lavine said. “This program grant will help us pursue the development of therapies and ways to treat heart failure that weren’t possible before.”
Lavine’s lab recently published several studies outlining key research themes that the grant will continue to support.
In one study, Lavine and his colleagues showed that a protein called CCL17 worsens heart damage by suppressing the action of specialized immune cells called regulatory T cells. These cells reduce inflammatory responses when the heart is damaged. The study, published in the journal Circulation, suggests that inhibiting CCL17 could help resolve heart inflammation after the heart has been injured by a heart attack, for example, and ultimately improve organ recovery. Lavine is working with industry collaborators to develop antibodies that bind to and neutralize CCL17 to reduce its pro-inflammatory actions.
“If you can resolve inflammation sooner, you may be able to facilitate heart muscle healing, which will improve longevity and function after a heart attack,” said Lavine, also director of the Cardiovascular Precision Medicine Research Initiative in the Cardiovascular Division. “The hope is that blocking inflammation early may reduce fibrosis – the formation of scar tissue – and improve long-term heart function.”
A second study, published in the journal Nature Cardiovascular Research, uses the latest single cell technologies to create the first comprehensive cellular atlas of human heart failure. Lavine and his team sequenced the hearts of 27 healthy donors and the hearts of 18 patients with dilated cardiomyopathy, a form of heart failure characterized by thinning and weakening of the heart muscle. The atlas is an important new resource for researchers trying to understand and develop better therapies for heart failure.
A third study, in the journal Development, demonstrated that researchers could use human pluripotent stem cells to create macrophages that recapitulate those from different parts of the body that have divergent effects on the heart. Lavine and her team hope to leverage this new system to engineer populations of macrophages that increase the ability to help repair or rejuvenate the heart.
“A number of groups have shown in animal models that stem cell-derived heart muscle cells can be grafted onto the heart,” Lavine said. “There’s potential for this to be therapeutic, but these cells don’t integrate well into the surrounding tissues and tend to cause arrhythmias. A key property of repair macrophages is their ability to help cells in tissues integrate – they can help connect cells electrically, which could eventually overcome current barriers that hinder stem cell therapies to repair or even regenerate parts of the human heart.”
Similar to how immune-based therapies have revolutionized the treatment of a number of cancers, this grant may be a step towards harnessing knowledge of the immune system to reduce cardiovascular inflammation and maximize the potential for regeneration of the human heart.