Targeting B cells of the pericardium to improve outcome post-myocardial infarction
Lead Research Organisation:
University of Edinburgh
Department Name: Centre for Cardiovascular Science
Abstract
Heart attack is the cause of as many as 100,000 hospital admissions each year in the UK. While most people survive, the injury results in loss of heart muscle and scarring putting patients at increased risk of chronic heart failure. After a heart attack, the body mounts an inflammatory response to clear dying tissue and repair the damage to the heart. This is a very important process as it determines how well the heart will heal and the patients risk of developing heart failure. Therapeutic strategies targeting specific aspects of the inflammatory response after a heart attack may prove particularly effective to improve heart repair and reduce risk of developing chronic heart failure.
The heart is enveloped by a protective sac called the pericardium. We have discovered that the outer-layer of the pericardium, also called parietal pericardium, has important immunologic properties. In particular, it contains a type of white blood cell called B cells, well known for their role in the production of antibodies during infection and after vaccination. Pre-clinical models have now shown that B cells of the parietal pericardium can control the immune cell response triggered by a heart attack and help repair the heart. Thus, targeting these B cells to boost their protective properties post-heart attack to improve cardiac outcome has clear clinical translation. To develop such treatments, we need to better understand the B cells of the parietal pericardium in humans.
In this project, we will work with surgeons performing heart operations to obtain fat samples from the pericardium from consenting patients. We will work out exactly how human pericardial B cells are activated after heart attack and identify the key proteins that control their protective function. We also want to identify the molecules that activates these B cells so that we can target them. This could be done using liposomes or lipid nanoparticles resembling those used to deliver COVID-19 mRNA vaccine. We will test whether specific substances added to liposomes can activate pericardial B cells and boost their protective function. Using a pre-clinical model of heart attack, we will test if these substances can improve healing of the heart and preserves its function after heart attack. We believe that this work will lead to the development of a new way of treating heart attack.
The heart is enveloped by a protective sac called the pericardium. We have discovered that the outer-layer of the pericardium, also called parietal pericardium, has important immunologic properties. In particular, it contains a type of white blood cell called B cells, well known for their role in the production of antibodies during infection and after vaccination. Pre-clinical models have now shown that B cells of the parietal pericardium can control the immune cell response triggered by a heart attack and help repair the heart. Thus, targeting these B cells to boost their protective properties post-heart attack to improve cardiac outcome has clear clinical translation. To develop such treatments, we need to better understand the B cells of the parietal pericardium in humans.
In this project, we will work with surgeons performing heart operations to obtain fat samples from the pericardium from consenting patients. We will work out exactly how human pericardial B cells are activated after heart attack and identify the key proteins that control their protective function. We also want to identify the molecules that activates these B cells so that we can target them. This could be done using liposomes or lipid nanoparticles resembling those used to deliver COVID-19 mRNA vaccine. We will test whether specific substances added to liposomes can activate pericardial B cells and boost their protective function. Using a pre-clinical model of heart attack, we will test if these substances can improve healing of the heart and preserves its function after heart attack. We believe that this work will lead to the development of a new way of treating heart attack.
Technical Summary
Inflammation is the crucial determinant of the extent of damage, repair, scarring and revascularisation of the heart post-myocardial infarction (MI). Until recently, little attention was given to the pericardium. Our published work established that the parietal pericardium is an important immune site, rich in a subset of B cells called B1 cells, most of which produce antibodies recognising phospholipids. In mice, B1 cells of the parietal pericardium are pro-reparative and promotes healing of the heart post-MI. However, development of translational applications targeting B1 cells have been impaired due to poor characterisation of the immune cell content of the human pericardium and of the equivalent of murine B1 cells.
Our preliminary data obtained from human biopsies and in mouse model of MI led us to hypothesise that B cells from the parietal pericardium play a critical role in the recruitment and "education" of immune cells important for repair of the heart post-MI and that they can be targeted to improve repair and function post-MI. In this project, we will characterise the pathways regulating the recruitment and education of immune cells by parietal pericardium B cells in humans. We will analyse the anti-phospholipid reactivity of human PP-AT B cells and test whether these can be activated in vitro using liposomes containing phospholipids. We will demonstrate the importance of novel factors in potentiating the reparative properties of human parietal pericardium B cells. We will finally show in mice that the parietal pericardium acts as a gateway for immune cells to the heart post-MI and provide proof of principle evidence that parietal pericardium B1 cells can be targeted using liposomes to increase the generation of reparative cells and promote cardiac repair post-MI.
In future, the protective properties of parietal pericardium B cells could be leveraged using liposomes or lipid nanoparticles to improve cardiac outcome in patients who had a recent MI.
Our preliminary data obtained from human biopsies and in mouse model of MI led us to hypothesise that B cells from the parietal pericardium play a critical role in the recruitment and "education" of immune cells important for repair of the heart post-MI and that they can be targeted to improve repair and function post-MI. In this project, we will characterise the pathways regulating the recruitment and education of immune cells by parietal pericardium B cells in humans. We will analyse the anti-phospholipid reactivity of human PP-AT B cells and test whether these can be activated in vitro using liposomes containing phospholipids. We will demonstrate the importance of novel factors in potentiating the reparative properties of human parietal pericardium B cells. We will finally show in mice that the parietal pericardium acts as a gateway for immune cells to the heart post-MI and provide proof of principle evidence that parietal pericardium B1 cells can be targeted using liposomes to increase the generation of reparative cells and promote cardiac repair post-MI.
In future, the protective properties of parietal pericardium B cells could be leveraged using liposomes or lipid nanoparticles to improve cardiac outcome in patients who had a recent MI.