Defining the effects of transplant immunosuppressants on innate immunity to fungi

器官移植是一种越来越常见的治疗一系列疾病的方法，但需要个人终身服用免疫抑制药物。这些药物阻止了免疫系统对移植的排斥，但增加了对危及生命的侵袭性真菌感染的易感性。这些感染的总死亡率超过40%，需要长期进行剧毒、昂贵的抗真菌治疗。了解使一些患者易患这些感染的免疫学机制对于改善结果至关重要。这项研究与侵袭性真菌感染有关，特别是侵袭性曲霉病。侵袭性曲霉病已成为发达国家最常见的致死真菌感染，死亡率高达40%至90%。据估计，英国每年有3000至4000人死于这种疾病。侵袭性曲霉病几乎只发生在免疫功能低下的患者中，实体器官移植患者已经成为快速增长的危险人群。这项研究正在试图确定导致移植患者真菌感染风险增加的机制。这些患者接受的主要免疫抑制药物被称为钙调神经磷酸酶抑制剂，被认为主要抑制T细胞获得性免疫反应。然而，最近的研究表明，钙调神经磷酸酶抑制剂可以对被称为吞噬细胞的免疫细胞产生重大影响。这是因为钙调神经磷酸酶途径需要通过一组被称为C型凝集素的吞噬细胞免疫传感分子来传递信号。这一点非常重要，因为一系列真菌病原体是通过C型凝集素受体(如Dectin-1)感知的。这项研究将调查这些药物如何干扰吞噬细胞感知和杀死真菌病原体，并将进一步定义钙调神经磷酸酶依赖的机制，一旦识别出真菌病原体，就会介导杀戮。这项研究很重要，因为侵袭性真菌感染是越来越多的移植患者和其他接受钙调神经磷酸酶抑制免疫抑制药物维持治疗的患者组死亡的主要原因。了解导致对这些感染易感性增加的机制将使我们能够开发新的策略，以确定患者何时处于危险之中，以及当真菌免疫严重受损时如何最好地恢复它。此外，确定这些药物对吞噬细胞功能的影响可能会进一步深入了解移植排斥反应，并可能对移植免疫和真菌免疫产生更广泛的影响。这项研究将由阿南德·沙阿博士通过临床研究奖学金进行。沙阿博士是哈里菲尔德医院的一名初级医生，专攻呼吸道感染和移植。他的奖学金将由帝国理工学院的Sunil Shaunak教授、Darius Armstrong-James博士和Elaine Bignell博士、阿伯丁大学的Gordon Brown教授和Harefield医院的Anna Reed博士支持。肖纳克教授是专注于转化医学发展的传染病临床学术带头人。阿姆斯特朗-詹姆斯博士是MRC真菌免疫学临床科学家，他开发了一种相关的真菌感染移植模型。布朗教授是一位著名的真菌免疫学家，他发现了C型凝集素真菌传感器Dectin-1。里德博士是哈里菲尔德医院的一名肺移植医生。这项研究将主要集中在一种新的基于钙调神经磷酸酶抑制剂的侵袭性曲霉病小鼠模型上。这个模型将被用来确定钙调神经磷酸酶抑制剂药物对真菌吞噬细胞的杀伤作用，以及这在曲霉病中是如何受到影响的。此外，我们在Harefield医院通过对患有侵袭性曲霉病的肺移植患者进行有针对性的观察研究，得到了伦理学上的批准，以证实基于模型的研究结果。

Organ transplantation is an increasingly common treatment for a range of diseases, but requires that individuals take life-long immunosuppressive medication. These drugs stop the immune system rejecting the transplant, but increase susceptibility to life-threatening invasive fungal infections. These infections have a mortality in excess of 40% overall, and require a long duration of highly toxic, expensive anti-fungal therapy. Understanding the immunological mechanisms that predispose some patients to these infections is critical to improving outcome.The research is relevant to invasive fungal infection and specifically invasive aspergillosis. Invasive aspergillosis has emerged as the commonest fungal infection causing death in developed countries, with a mortality of 40% to 90%. There are estimated to be 3000 to 4000 deaths from this disease per annum in the UK. Invasive aspergillosis almost exclusively occurs in immunocompromised patients, and solid organ transplant patients have emerged as a rapidly growing at risk population.The research is trying to define the mechanisms that lead to increased risk of fungal infection in transplant patients. The main immunosuppressive drugs these patients receive are called calcineurin inhibitors which are thought to primarily suppress T cell adaptive immune responses. However recent studies have demonstrated that calcineurin inhibitors could have major effects on immune cells called phagocytes. This is because the calcineurin pathway is required for signalling through a group of phagocyte immune sensing molecules called C-type lectins. This is very important because a range of fungal pathogens are sensed through C-type lectin receptors such as Dectin-1. The research will investigate how these drugs interfere with phagocyte sensing and killing of fungal pathogens and will further define the calcineurin-dependent mechanisms that mediate killing once a fungal pathogen has been recognised. This research is important because invasive fungal infections are a major cause of mortality in an expanding group of transplant patients and within other patient groups on maintenance therapy with calcineurin inhibitor immunosuppressive drugs. Understanding the mechanisms that lead to increased susceptibility to these infections will enable us to develop new strategies to identify when patients become at risk, and how best to restore fungal immunity when it becomes critically impaired. Furthermore defining the effects of these drugs on phagocyte function may lead to further insights into transplant rejection and is likely to have wider implications for transplant immunity as well as fungal immunity.The research will be carried out by Dr Anand Shah through a Clinical Research Fellowship. Dr Shah is a junior doctor specialising in respiratory infection and transplantation at Harefield Hospital. His fellowship will be supported by Prof. Sunil Shaunak, Dr Darius Armstrong-James and Dr Elaine Bignell at Imperial College, Professor Gordon Brown at the University of Aberdeen, and Dr. Anna Reed at Harefield Hospital. Professor Shaunak is a leading Infectious Diseases Clinical Academic focussed on translational medicine development. Dr Armstrong-James is an MRC Clinician Scientist in fungal immunology who has developed a relevant transplant model of fungal infection. Professor Brown is a renowned fungal immunologist who discovered the C-type lectin fungal sensor Dectin-1. Dr. Reed is a lung transplant physician at Harefield Hospital.The research will be primarily focussed on a new calcineurin inhibitor based mouse model of invasive aspergillosis. This model will be used to define the effects of calcineurin inhibitor drugs on phagocyte killing of fungi, and how this is affected in aspergillosis. In addition, we have ethical approval to confirm the model-based findings through targeted observational studies of lung transplant patients with invasive aspergillosis at Harefield Hospital.