iNKT cells as drivers for preterm labour

这项工作的目的是开发预防早产的治疗方法。早产是一个严重的健康问题。在全球范围内，每年有100多万儿童死于早产并发症。在英国，约有5.5万名婴儿（约占英国新生儿总数的7.8%）早产。尽管付出了很多努力，但这些比率仍在上升。尽管存活率正在提高，77%的英国26周出生的婴儿现在已经出院，但幸存者面临着短期发病和长期残疾的风险增加。长期残疾包括呼吸问题、运动和感觉障碍、学习困难以及社交和行为困难，不仅是由早产的后果造成的，而且是由早产之前的宫内炎症造成的。据估计，在英格兰和威尔士，早产并发症每年给公共财政造成29.46亿英镑的损失（2006年价格）。不幸的是，几乎没有任何治疗早产的方法。即使我们对所有有风险的妇女使用目前所有的治疗方法，英国的早产率也只会下降0.2%，即从7.8%降至7.6%。我们和其他人都认为，缺乏良好的治疗，以及在发育过程中缺乏治疗是因为我们没有正确地理解是什么导致了女性早产，也不知道是什么引发了足月分娩。我们和其他人已经表明，“炎症”是分娩开始的关键，无论是足月还是早产。我们已经尝试了几种治疗炎症从而预防早产的策略，但没有一种有效。我们认为这是因为我们试图在炎症开始后很好地阻止它。我们现在要看一些免疫细胞它们参与了炎症过程的开始并且在小鼠模型中被证明对刺激早产很重要。这些细胞（不变的NKT细胞）很重要，因为它们连接了免疫系统的两个部分，而且它们可以对“危险”信号迅速作出反应，包括孕妇的信号。在这项研究中，我们将在我们认为分娩开始的地方观察这些细胞——将母亲和婴儿分开的子宫内膜。我们会看到分娩时子宫内膜发生了什么，然后看看分娩时子宫内膜中的iNKT细胞是如何变化的。我们将看看能否通过刺激iNKT细胞在小鼠模型中开始分娩，然后看看阻止iNKT激活的药物是否能防止炎症引起的早产。接下来，我们将观察这些iNKT细胞是否在分娩过程的早期被激活——我们认为会的。最后，我们将看到目前用于治疗一些妇女早产的黄体酮如何影响iNKT细胞。我们相信，我们的工作将产生对分娩如何开始的新理解，从而最终开发出预防早产的治疗方法。这种治疗方法可在防止每年多达100万儿童死亡方面取得重大进展。

The purpose of this work is to develop treatments to prevent preterm birth. Preterm birth is a big health problem. Globally, over 1 million children die each year from the complications of preterm birth. In the UK around 55,000 babies (around 7.8% of all UK births) are born preterm. Despite much effort, these rates are rising. Although survival rates are improving, with 77% of UK babies born at 26 weeks gestation now leaving hospital, survivors are at increased risk of short term morbidity and long term disability. Long term disability includes respiratory problems, motor and sensory impairment, learning difficulties, and social and behavioral difficulties and is driven not only by the consequences of prematurity, but by the intrauterine inflammation which precedes prematurity. Together the complications of preterm birth result in a £2.946 billion estimated annual costs of preterm birth to the public purse in England and Wales (2006 prices). Unfortunately, there are hardly any treatments in development for preterm birth. Even if we use all the treatments we currently have for all women at risk, preterm birth rates will only fall by 0.2% in the UK i.e., from 7.8% to 7.6%. We and others have suggested that this lack of good treatments, and the lack of treatments in development is because we don't properly understand what causes women to go into preterm labour, nor do we understand what triggers labour at term.We and others have shown that "inflammation" is key to the start of labour, both at term and preterm. We have tried several strategies to treat inflammation and hence prevent preterm labour, but none has yet been effective. We think this is because we are trying to stop inflammation well after it has started. We are now going to look at some immune cells which are involved in the start of the inflammatory process and which have been shown to be important in stimulating preterm labour in a mouse model. These cells (invariant [i] NKT cells) are important because they link two halves of the immune system, and because they can respond rapidly to "danger" signals, including those present in pregnant women.In this study we are going to look at these cells in the place that we think that labour starts - the lining of the womb which separates mother from baby. We will see what happens in the lining of the womb in labour, and then look at how the iNKT cells change in the lining of the womb in labour. We will see if we can start labour in a mouse model by stimulating these iNKT cells, and then see if drugs which prevent iNKT activation can prevent inflammation induced preterm labour. Next, we will look to see if these iNKT cells are activated early in the process of labour - we think they will be. Lastly, we will see how progesterone, which is currently used to treat preterm labour in some women, might affect iNKT cells.We believe our work will generate new understanding of how labour starts, and so ultimately develop treatments to prevent preterm labour. Such treatments could make major inroads into preventing the deaths of up to 1 million children per year.