Transplant for Life - Advancing HLA Matching in Paediatric Kidney Transplantation using Molecular Assessment of HLA Immunogenicity

第一次成功的肾脏移植手术是在1954年进行的，这是由于同卵双胞胎Herrick兄弟的完美组织匹配（或HLA匹配-允许身体区分自身和他人的蛋白质）。从那时起，肾移植已成为成千上万终末期肾病患者的最佳治疗方法。这种压倒性的成功主要归功于对HLA系统的更好理解，检测攻击供体组织蛋白的抗体的改进技术，以及抗排斥药物的改进。然而，长期结果在很大程度上保持不变，大多数移植由于排斥而丢失，平均时间为12年。这主要是由于供体和受体HLA蛋白之间的不相容性。儿科受者受益于成人移植的研究。然而，成人和儿童之间存在根本差异。儿童肾衰竭的主要原因与成人不同，成人经常患有慢性疾病，如糖尿病和心血管疾病。因此，儿童移植更健康。他们需要更长时间的移植，当第一次移植停止工作时，他们将需要第二次，第三次或更多。儿童从移植中获得最多的“额外寿命”。一个在5岁时接受移植的孩子预计可以活几十年。因此，与移植相关的利益和风险在更长的时间范围内被放大。HLA分型目前作为称为血清型的广泛组进行，并记录为一个字段HLA类型。例如，A组最常见的HLA类型是HLA-A2。但我们现在知道有许多不同类型的HLA-A2。这被记录为两个字段HLA类型，例如HLA-A*02：01、HLA-A*02：02等。因此，当仅在血清学水平进行匹配时，供体和受体之间的匹配（和错配）可能不完全精确。通过使用现代计算方法（通常称为分子HLA配型），两个字段HLA类型可用于更详细的配型评估。这类似于使用显微镜而不是放大镜来比较HLA分子。我们的团队已经开发了新的方法来评估供体和受体HLA分子之间的差异，基于我们对它们的3D结构和表面电荷的研究。该工具能够判断是否存在可能导致排斥（免疫原性）的大差异，或者差异实际上很小。因此，分子HLA配型的好处是双向的-通过提高选择良好错配的信心，并通过允许使用低免疫原性HLA错配来增加找到合适供体的机会。本研究旨在评估分子HLA配型在儿童和青年肾移植患者中的有效性，即确定发生抗HLA抗体和排斥反应的风险，并预测肾功能恶化的风险。我们将使用2010-2015年儿科患者的同期数据集开发风险预测模型。将在澳大利亚和新西兰的类似患者队列中测试该模型的有效性和可靠性。然后将在英国移植登记处（2000-2015）的儿科患者组中回顾性测试个体风险模型，以预测肾移植失败的风险。我们的目标是推导出一个分子供体-受体HLA匹配评分，该评分可用于国家肾脏分配计划，为儿童提供更好的HLA匹配肾脏;并根据儿童的排斥风险调整其抗排斥药物，从而允许对儿童进行个性化治疗。

The first successful kidney transplant was performed in 1954 and was made possible due to the perfect tissue match (or HLA match - the proteins that allow the body to tell the difference between itself and others) from identical twins, the Herrick brothers. Since then, kidney transplantation has become the best treatment for thousands of patients with end stage kidney disease. This overwhelming success is largely due to better understanding of the HLA system, improved techniques to detect antibodies which attack donor tissue proteins, and improvements in anti-rejection medication. However, long term outcomes have largely remained unchanged and the majority of transplants are lost due to rejection at an average time of 12 years. This is mainly due to incompatibilities between donor and recipient HLA proteins. Paediatric recipients have benefitted from research that has been done in adult transplantation. Nevertheless, there are fundamental differences between adults and children. The main causes of kidney failure in children are different compared to adults who often suffer from chronic ill health such as diabetes and cardiovascular disease. Therefore, children come into transplantation healthier. They need transplants that last longer and when the first transplant stops working, they will need a second, third or more. Children gain the most 'added life years' from transplantation. A child who has a transplant at age 5 years is expected to live many decades. Thus, benefits and risks related to transplantation are magnified over a larger time horizon. HLA typing is currently done as broad groups called serotypes and recorded as a one field HLA type. For example, the most common HLA type for group A is HLA-A2. But we now know there are many different types of HLA-A2. This is recorded as a two field HLA type, e.g. HLA-A*02:01, HLA-A*02:02 etc. Thus, when matching is only done at the serology level, the match (and mismatch) between donor and recipient might not be entirely precise. The two field HLA type can be used for more detailed assessment of matching by using modern computational approaches, often referred to as molecular HLA matching. This is akin to using a microscope rather than a magnifying glass to compare the HLA molecules. Our team has developed new ways to assess the difference between donor and recipient HLA molecules based on our research into their 3D structure and surface charge. The tool is able to tell if there is a big difference which can cause rejection (immunogenicity) or if the difference is actually quite small. Therefore the benefits of molecular HLA matching work both ways - by improving confidence in selecting a good mismatch, and increasing the chances of finding a suitable donor by allowing low immunogenicity HLA mismatches to be used. This study aims to assess the effectiveness of molecular HLA matching in children and young adults with kidney transplants, i.e. to determine the risk of developing anti-HLA antibodies and rejection, and to predict the risk of deteriorating kidney function. We will develop the risk prediction model using a contemporaneous dataset of paediatric patients from 2010-2015. The model will be tested for validity and reliability in a similar cohort of patients from Australia and New Zealand. The individual risk model will then be tested retrospectively in the group of paediatric patients in the UK Transplant Registry (2000-2015) to predict the risk of kidney transplant failure. We aim to derive a molecular donor-recipient HLA matching score which can be used in the national kidney allocation scheme to provide children with better HLA matched kidneys; and to allow individualised treatment of children by enabling adjustments to their anti-rejection medication according to their risk of rejection.