A multi-disciplinary approach to understanding the immunological basis and potential prevention of graft versus host disease.

免疫系统包含不同类型的白色血细胞，它们共同抵抗疾病。这些细胞是从健康人骨髓中的干细胞生长而来的。然而，在一些人中，一些干细胞和白色血细胞会癌变，导致白血病。为了治疗这种疾病，患者的干细胞和白色细胞通过放射和/或化疗去除。这杀死了癌细胞，但也杀死了其他健康的白色细胞，这些细胞对抵抗感染很重要。为了解决这个问题，患者接受了来自健康志愿者的干细胞移植。干细胞进入患者的骨髓并分化成白色血细胞，给患者一个新的免疫系统。干细胞转化为白色血细胞的速度越快，白色细胞的数量增加得就越快。这就是所谓的免疫重建。产生的“有用的”白色细胞（例如可以杀死癌细胞的细胞）越多，白血病复发的机会就越小，患者因其他感染而生病的可能性就越小。这种杀死癌症的过程被称为移植物抗白血病（GVL）。移植物抗宿主病（GVHD）是干细胞移植（SCT）后的一种重要临床并发症，由同一供体白色细胞攻击它们识别为“外来”的患者引起。这导致患者发病率和死亡率显著增加，并显著影响其生活质量。然而，由于GVHD的过程与介导GVL的过程相同，目前阻止白色细胞攻击患者组织的治疗也阻止相同的细胞杀死癌细胞。这使患者从原始疾病复发的风险增加。现在很清楚，需要开发预防GVHD但不阻止GVL的治疗方法。移植物抗宿主病具有影响皮肤、肠道和肝脏的特征性临床表现，我们的工作表明，特定的分子将患者的白色细胞引导到这些组织，在那里它们造成损伤。因此，预防GVHD的一种策略是防止白色细胞进入它们可能造成损害的组织。关键是癌细胞将存在于血液和骨髓中，而不是组织中，因此这种策略不应该预防GVL。在我们最近的研究中，我们一直在监测疾病发展之前的免疫重建，我们的数据表明，这是预测哪些患者将发展疾病的关键。在这里，我们将联合收割机结合我们的免疫重建的研究与我们的白色细胞运动到组织的研究，以a）预测哪些患者将发展GVHD，B）在哪些组织中他们将发展疾病和c）开发策略来阻止白色细胞运动到组织。将在移植后的前2周内监测将杀死组织和肿瘤的白色细胞的发展。我们将专门分析供体白色细胞的重建，评估它们如何移动到组织中以及它们到达后会做什么。重要的是，我们可以获得捐赠者和患者的血液和组织，包括皮肤，肠道，肝脏和骨髓。一旦我们确定了白色细胞是如何到达组织的，我们将测试一些方法来防止这种情况。我们有很好的条件将这项工作转化为临床。癌症科学学院包括英国最大的癌症试验单位之一，汇集了来自整个大学的临床试验专业知识，特别是三个大型，完善的，UKCRC完全注册的临床试验单位。因此，我们设想这项工作可以成功和迅速地翻译。这将显著提高干细胞移植后患者的预后和福利。

The immune system contains different types of white blood cell that work together to fight off disease. These cells grow from stem cells in the bone marrow of healthy people. However, in some people, some of the stem cells and white blood cells become cancerous and this results in leukaemia. In order to treat this, the patient's stem cells and white cells are removed with irradiation and/or chemotherapy. This kills the cancerous cells but it also kills the other healthy white cells that are important for fighting off infections. To remedy this, the patient receives a stem cell transplant from a healthy volunteer. The stem cells go to the patient's bone marrow and differentiate into white blood cells, giving the patient a new immune system. The quicker the stem cells turn into white blood cells, the faster the number of white cells increases. This is called immune reconstitution. The more 'useful' white cells (e.g. ones that can kill cancer cells) that are produced, the less chance there is of the leukaemia recurring and the less likely the patient is to become sick due to other infections. This process of cancer killing is called Graft versus Leukaemia (GVL).Graft-versus-host disease (GVHD) is an important clinical complication following stem cell transplantation (SCT), caused by the same donor white cells attacking the patient whom they recognise as 'foreign'. This results in significant patient morbidity and mortality and significantly affects their quality of life. However as the process of GVHD is the same as that which mediates GVL, current treatments which stop white cells attacking the patient tissues also stop the same cells from killing cancerous cells. This puts patients at an increased risk of relapse from the original disease. It is now clear that treatments need to be developed which prevent GVHD, but which do not stop GVL. GVHD has a characteristic clinical picture affecting the skin, gut and liver and our work shows that specific molecules guide patient white cells to these tissues where they cause damage. Therefore one strategy to prevent GVHD is to prevent the white cells getting to the tissues where they can cause damage. Key to this is that cancerous cells will be present in the blood and bone marrow and not in the tissues and therefore this strategy should not prevent GVL. In our recent studies we have been monitoring immune reconstitution prior to disease development and our data indicate that this is key to predicting which patients will develop disease. Here we will combine our studies of immune reconstitution with our studies of white cell movement to the tissue to a) predict in which patients GVHD will develop, b) in which tissues they will develop disease and c) develop strategies to block movement of the white cells to the tissues.The development of white cells which will kill tissues and tumour will be monitored during the first 2 weeks following transplant. We will specifically analyse reconstitution of donor white cells, assessing how they move to the tissues and what they do once they have arrived. Importantly for this programme we have access to both donor and patient blood and tissues including skin, gut, liver and bone marrow. Once we have determined how white cells get to the tissues we will test out a number of methods to prevent this. We are in an excellent position to translate this work to the clinic. The School of Cancer Sciences encompasses one of the largest cancer trials units within the UK bringing together clinical trial expertise from across the University and, in particular, the three large, well-established, UKCRC fully-registered Clinical Trials Units. Therefore we envisage that this work can be successfully and rapidly translated. This will significantly enhance patient outcome and welfare following stem cell transplant.