iNKT cells as drivers for preterm labour

iNKT 细胞作为早产的驱动因素

• 批准号: MR/L002647/1
• 负责人: Jane Norman
• 金额: $ 16.03万
• 依托单位: University of Edinburgh
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2013
• 资助国家: 英国
• 起止时间: 2013 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FL002647%2F1
• 关键词: iNKT; cells; drivers; preterm; labour

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.

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55，000名婴儿（约占英国出生人口的7.8%）早产。尽管付出了很大努力，这些比率仍在上升。虽然存活率正在提高，77%的英国婴儿在妊娠26周时出生，现在离开医院，幸存者的短期发病率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、学习困难以及社会和行为困难，不仅是由早产的后果造成的，而且是由早产前的宫内炎症造成的。早产并发症导致英格兰和威尔士公共财政每年估计早产费用为29.46亿英镑（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%，从7.8%下降到7.6%。我们和其他人认为，这种缺乏良好的治疗方法，以及缺乏发育中的治疗方法是因为我们没有正确理解是什么原因导致妇女进入早产，我们也不知道是什么触发了足月分娩。我们和其他人已经表明，“炎症”是分娩开始的关键，无论是在足月还是早产。我们已经尝试了几种策略来治疗炎症，从而预防早产，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炎症。我们现在将研究一些免疫细胞，它们参与炎症过程的开始，并且已被证明在小鼠模型中刺激早产方面很重要。这些细胞（不变的NKT细胞）非常重要，因为它们连接着免疫系统的两个部分，并且它们可以对“危险”信号做出快速反应，包括孕妇体内的那些。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。我们将看到在分娩时子宫内膜发生了什么，然后看看iNKT细胞在分娩时子宫内膜的变化。我们将看看我们是否可以通过刺激这些iNKT细胞在小鼠模型中开始分娩，然后看看阻止iNKT激活的药物是否可以预防炎症诱导的早产。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-我们认为它们会被激活。最后，我们将看到孕酮，这是目前用于治疗早产的一些妇女，可能会影响iNKT细胞。我们相信我们的工作将产生新的理解如何劳动开始，从而最终开发治疗，以防止早产。这种治疗方法可以在防止每年多达100万儿童死亡方面取得重大进展。

项目成果

15-epi-lipoxin A4 reduces the mortality of prematurely born pups in a mouse model of infection-induced preterm birth.

• DOI: 10.1093/molehr/gau117
• 发表时间: 2015-04
• 期刊: Molecular human reproduction
• 影响因子: 4
• 作者: Rinaldi SF;Catalano RD;Wade J;Rossi AG;Norman JE
• 通讯作者: Norman JE

Crosstalk between monocytes and myometrial smooth muscle in culture generates synergistic pro-inflammatory cytokine production and enhances myocyte contraction, with effects opposed by progesterone.

• DOI: 10.1093/molehr/gav027
• 发表时间: 2015-08
• 期刊: Molecular human reproduction
• 影响因子: 4
• 作者: Rajagopal SP;Hutchinson JL;Dorward DA;Rossi AG;Norman JE
• 通讯作者: Norman JE

Decidual neutrophil infiltration is not required for preterm birth in a mouse model of infection-induced preterm labor.

• DOI: 10.4049/jimmunol.1302891
• 发表时间: 2014-03-01
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Rinaldi SF;Catalano RD;Wade J;Rossi AG;Norman JE
• 通讯作者: Norman JE

Immune cell and transcriptomic analysis of the human decidua in term and preterm parturition.

• DOI: 10.1093/molehr/gax038
• 发表时间: 2017-10-01
• 期刊: Molecular human reproduction
• 影响因子: 4
• 作者: Rinaldi SF;Makieva S;Saunders PT;Rossi AG;Norman JE
• 通讯作者: Norman JE