Targeting B cells of the pericardium to improve outcome post-myocardial infarction

在英国，心脏病发作是每年多达10万人入院的原因。虽然大多数人都能存活下来，但这种损伤会导致心肌损失和疤痕，使患者患慢性心力衰竭的风险增加。心脏病发作后，身体会产生炎症反应，以清除垂死的组织并修复心脏损伤。这是一个非常重要的过程，因为它决定了心脏的愈合情况以及患者发生心力衰竭的风险。针对心脏病发作后炎症反应的特定方面的治疗策略可能被证明对改善心脏修复和降低慢性心力衰竭的风险特别有效。心脏被称为心包的保护囊包裹。我们发现心包的外层，也称为壁层心包，具有重要的免疫学特性。特别是，它含有一种称为B细胞的白色血细胞，众所周知，它们在感染期间和接种疫苗后产生抗体。临床前模型现在已经表明，心包壁层的B细胞可以控制心脏病发作引发的免疫细胞反应，并帮助修复心脏。因此，靶向这些B细胞以增强其在心脏病发作后的保护特性以改善心脏结果具有明确的临床转化。为了开发这种治疗方法，我们需要更好地了解人类心包壁层的B细胞。在本项目中，我们将与进行心脏手术的外科医生合作，从同意的患者心包中获取脂肪样本。我们将研究出心脏病发作后人类心包B细胞是如何被激活的，并确定控制其保护功能的关键蛋白质。我们还想确定激活这些B细胞的分子，这样我们就可以靶向它们。这可以使用类似于用于递送COVID-19 mRNA疫苗的脂质体或脂质纳米颗粒来完成。我们将测试添加到脂质体中的特定物质是否可以激活心包B细胞并增强其保护功能。使用心脏病发作的临床前模型，我们将测试这些物质是否可以改善心脏的愈合并在心脏病发作后保留其功能。我们相信，这项工作将导致开发一种治疗心脏病发作的新方法。

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.