Pilot study to develop a novel model to investigate the mechanisms and consequences of foetal immune programming on immune fitness through life

免疫系统在生命早期如何发育对于确定整个成年期的免疫适应性至关重要。我们在生命早期接触到的免疫挑战在训练免疫系统方面起着重要的作用，教会它对什么做出反应，以及反应的强度。保持这种平衡对成年人的健康至关重要，因为免疫失调会导致过敏、自身免疫、精神疾病和肥胖等疾病。妊娠期是胎儿免疫发育的关键时期，母亲所面临的免疫挑战影响着婴儿免疫系统的发育。母亲的感染会改变胎儿的免疫发育，并可能改变后代成年后对感染和过敏的反应方式。我们的小组研究寄生虫的免疫，这是一个巨大的全球人类健康负担，也是畜牧业的巨大经济负担。它们非常善于逃避或抑制免疫反应，使它们能够在宿主体内存活数十年。众所周知，母体蠕虫感染会影响胎儿的免疫发育，并可能抑制后代的免疫，导致晚年免疫反应水平降低。这可能使他们更容易受到未来的感染，也可能削弱他们对疫苗接种的反应能力。然而，它也有有益的作用，可以使他们不那么容易过敏。然而，发生这种情况的机制尚不清楚。不幸的是，在人类身上进行机械工作非常困难，而且缺乏实验动物模型。这项提议的目标是开发一种新的小鼠模型，使我们能够研究怀孕期间蠕虫感染如何影响婴儿免疫系统的发育，以及这如何影响他们成年后的免疫平衡和健康。这将有助于确定为什么怀孕期间的一些免疫挑战会关闭婴儿的免疫反应，增加感染易感性，降低疫苗反应性和患疾病的风险，而其他免疫挑战会激活婴儿的免疫系统，增加他们以后生活中患病的风险。这将增加我们的基础知识，这些知识可用于识别早期疾病相关的风险标记，使我们能够预测晚年的健康状况。它还可以用来建议在生命早期操纵免疫发育的策略，以防止个体随后患上疾病。确定母体蠕虫感染如何抑制后代对疫苗接种的反应能力，对于制定针对牲畜和人类中蠕虫和非蠕虫感染的疫苗战略具有重要意义。

How the immune system develops in early life is critical for defining immune fitness throughout adult life. The immune challenges which we are exposed to in early life play an important role in training the immune system, teaching it what to respond to, and how strongly to respond. Getting this balance right is critical for health in adult life, with dysregulated immunity leading to disease, such as allergies, autoimmunity, mental illnesses, and obesity.Foetal development during gestation is a critical period of immune development, and the immune challenges faced by the mother influence how the baby's immune system develops. Infections in the mother alter foetal immune development, and can change the way the offspring responds in adult life to infections and allergies. Our group studies immunity to parasitic worms, which are a huge worldwide human health burden, and large economic burden for the livestock industry. They are very good at evading or suppressing immune responses, allowing them to survive for decades in their host. Maternal helminth infections are known to influence foetal immune development, and can suppress offspring immunity resulting in a lower level of immune responsiveness in later life. This can make them more susceptible to future infections, and can also impair their ability to respond to vaccination. However, it can also have beneficial effects, and can make them less susceptible to allergies. However, the mechanisms by which this occurs are unknown.Unfortunately, it is very difficult to perform mechanistic work in humans, and there is a lack of experimental animal models. The goal of this proposal is to develop a new mouse model that will allow us investigate how helminth infection during pregnancy influences the development of the baby's immune system, and how this impacts their immune balance and health during adulthood. This will help identify why some immune challenges during pregnancy turn off the baby's immune responses, increasing infection susceptibility and lowering vaccine responsiveness and the risk of developing diseases, whilst other immune challenges activate the baby's immune system increasing their risk of diseases in later life. This will increase our fundamental knowledge, and this knowledge can be used to identify early-life disease associated risk markers allowing us to predict health in later life. It can also be used to suggest strategies to manipulate immune development during early life to prevent individuals subsequently developing disease. Identifying how maternal helminth infections inhibit the ability of offspring to respond to vaccinations is important for the development of vaccine strategies for helminth and non-helminth infections in both livestock and humans.