Haemoglobinopathies as a target for Fetal Transplantation

背景在英国，每年有200多名婴儿出生时患有遗传性血液疾病，如血红蛋白病。这些疾病会影响红细胞携带氧气的部分。地中海贫血是最常见的一种。治疗包括在患者一生中定期输血。这可能在以后的生活中导致多种问题，包括糖尿病、心脏病和由于组织中铁的过量积累而导致的骨骼变薄。此外，许多人需要复杂的多学科护理，由于住院和症状问题，对学校和工作造成相当大的干扰。目前，地中海贫血可以通过骨髓移植治愈。这包括提供供体干细胞，但这并不经常提供，因为有很大的风险。病人的免疫系统和移植的免疫细胞都可能导致严重的问题，包括死亡。移植物抗宿主病也有相当大的风险，其中移植细胞开始攻击受体。因此，有很多关于免疫系统在这种情况下的功能的研究。胎儿的免疫系统是独特的，因为它还在学习如何称呼朋友（“自我认知”或“宽容”）或敌人。研究已经表明，在这个时候进行移植可以使移植产生耐受性，而无需给予任何药物来抑制免疫系统，避免了许多产后骨髓移植的风险。然而，我们还不能用它来治疗像地中海贫血这样的血红蛋白病模型。我们的研究我们知道，干细胞不能单独植入或诱导耐受性，所以我的研究旨在观察骨髓中允许干细胞粘附或“植入”胎儿体内的其他细胞。我们将通过将骨髓移植到胎鼠体内并研究移植细胞在受体体内的表现来实现这一目标。在确定这一过程中的重要细胞后，我们将尝试用胎儿移植治疗地中海贫血小鼠模型。如果成功，小鼠将表达两种不同类型的红细胞（地中海贫血细胞和来自移植的细胞）。我们将能够通过检查小鼠的血液和骨髓来研究这些。重要的是，来自捐赠者的健康血细胞将意味着这些小鼠不会出现地中海贫血的症状，包括贫血和心肌损伤。如果我们能够鉴定出一种诱导胎儿移植耐受的特定细胞，我们将更接近于为人类提供地中海贫血和其他可在产前诊断的毁灭性疾病的治疗方法。事实上，虽然前者患者可以存活到成年，但在许多其他情况下（如罕见的代谢疾病），这种疾病可能在发育过程中不断发展。胎儿干细胞移植可以治愈这些疾病，因此在婴儿出生时也会有更好的结果。

BackgroundOver 200 babies are born each year in the UK with inherited blood disorders such as haemoglobinopathies. These disorders affect the oxygen carrying part of the red blood cell. Thalassaemia is one of the most common. Treatment involves regular blood transfusions throughout the life of the patient. This can lead to multiple issues in later life including diabetes, heart conditions and thinning of the bone due to excess accumulation of iron in the tissues. Furthermore, many individuals require complex multi-disciplinary care and have considerable disruption to school and work due to hospital admissions and problems with symptoms. At present, Thalassaemia can be cured with a Bone Marrow Transplant. This involves giving donor stem cells, however this is not offered very often because there are significant risks involved. The immune system of the patient and the immune cells in the transplant can both cause significant problems, including death. There is also a considerable risk of Graft vs Host Disease, wherein the transplanted cells begin to attack the recipient. For that reason, there is a lot of research into the way that the immune systems function in this setting. Fetal Stem Cell TransplantThe immune system of the fetus is unique, because it is still learning what it needs to call a friend ("self-recognition" of "tolerance") or an enemy. Research has already shown that giving a transplant at this time can give tolerance to the transplant without needing to give any medication to suppress the immune system, avoiding many of the risks of post-natal bone marrow transplant. However we have not been able to use this to treat a model for haemaglobinopathies like thalassaemia.Our Research We know that stem cells cannot engraft or induce tolerance alone, so my research aims to look at other cells within the bone marrow that allow the stem cells to stick or "engraft" within the fetus. We will do this by performing bone marrow transplants into fetal mice and studying how the transplanted cells behave in the recipient. After identifying the important cells in this process we will then attempt to treat a mouse model of thalassaemia with a fetal transplant. If successful, the mice will express two different types of red blood cell (Thalassaemia cells and cells from the transplant). We will be able to study these by examining both mice blood and bone marrow. Importantly, having healthy blood cells present from the donor will means these mice do not get symptoms of thalassaemia - including anaemia and heart muscle damage.Implications of this workIf we are able to identify a specific cell that induces tolerance for fetal transplantation, we will be much closer to delivering a treatment into humans for thalassemia and other devastating diseases which can be diagnosed prenatally. Indeed, while patients with the former will survive to adulthood, there are many other conditions (such as rare metabolic conditions) where the disease may be progressing during development. Fetal stem cell transplant would offer a cure for these conditions and therefore also a better outcome by the time the baby is born.