Role of epithelial HLA-G in lung transplantation

描述(由申请人提供)：肺移植是选定的终末期肺部疾病患者的救命选择。慢性同种异体移植排斥反应(闭塞性细支气管炎综合征，BOS)是长期存活的主要限制因素，但其发病机制尚不清楚，目前的治疗方法，包括有效的免疫抑制剂，大多无效。目前BOS的诊断依赖于临床认识和肺功能下降。这些标志物可能只有在BOS建立后才会出现变化，而临床诊断缺乏准确性导致治疗不充分或免疫抑制剂治疗不当，使患者面临致命感染的风险。一种非经典的人类白细胞抗原I类分子，即人类白细胞抗原-G，最先在胎盘的胎儿细胞中被发现，它与母体免疫细胞相互作用，在心脏、肾脏和肝脏移植中可能具有“耐受”功能，在这些器官移植中，人类白细胞抗原-G的表达与移植物存活有关。然而，人类白细胞抗原-G在肺移植存活中的作用一直没有被研究过，移植肺和宿主的人类白细胞抗原-G基因与蛋白表达在BOS发生发展过程中的关系也完全未知。由于呼吸道粘膜是异体肺与外部环境相互作用的主要部位，因此它是调节移植肺耐受性的唯一部位。人类白细胞抗原-G的表达可能通过调节肺内局部和循环免疫细胞，从而调节机体对感染和排斥的反应。我们认为循环中的人类白细胞抗原G和人类白细胞抗原G在移植肺中的表达有助于保护同种异体移植的排斥反应。我们进一步认为供者和宿主的人类白细胞抗原G基因都会影响人类白细胞抗原的表达水平。为了解决这一问题，我们提出了以下具体目标：目的1.肺移植后患者发生排斥反应的临床症状与循环中的sHLAG丢失和/或同种异体移植中的HLAG丢失有关。我们假设可以在肺移植后的患者中检测到循环中的HLA-G，低水平与第一年发生的急性排斥事件的数量较多相关，并且在排斥发生之前就已经降低了水平。我们还假设在原位和培养的呼吸道上皮细胞表达人类白细胞抗原-G。目的#2.在同种异体移植中，循环中的人类白细胞抗原-G和人类白细胞抗原-G的表达水平分别取决于宿主和供者的基因。我们假设，在肺移植前，人类白细胞抗原-G基因影响外周血中可溶性人类白细胞抗原-G的水平，供者和受者的基因对循环中的人类白细胞抗原-G的浓度有影响，并且与人类白细胞抗原-G低表达相关的基因型别将与较高的排斥风险相关。了解肺移植患者中人类白细胞抗原-G的表达及表达的基因决定因素可能有助于早期、更明确地诊断BOS，并有助于更好地了解肺移植免疫耐受。 相关性：对于选定的终末期肺部疾病患者，肺移植是一种挽救生命的选择，但新肺的排斥反应限制了长期生存。免疫系统的一种强有力的调节剂，人类白细胞抗原-G，可能在保护移植的肺免受宿主免疫系统的攻击方面发挥作用。我们认为，移植患者血液和新肺中的人类白细胞抗原-G有助于保护同种异体移植物免受排斥反应：如果是真的，我们的应用将引领未来的大规模临床试验，以确定人类白细胞抗原-G作为移植排斥反应的标记物的有用性，并可能作为移植患者的救命疗法。

DESCRIPTION (provided by applicant): Lung transplantation is a life-saving option for selected patients with end-stage lung disease. Chronic allograft rejection (bronchiolitis obliterans syndrome, or BOS) is the major limitation to long-term survival, yet its pathogenesis is poorly understood and current therapies, including potent immunosuppressive agents, are largely ineffective. The diagnosis of BOS currently depends on clinical recognition and decline in pulmonary function. These markers may manifest changes only after BOS has become established, and the lack of precision in the clinical diagnosis leads either to inadequate treatment or inappropriate treatment with immunosuppressive agents, exposing the patient to the risk of lethal infection. A non-classical HLA class I molecule, HLA-G, first discovered in the fetal cells of the placenta that interact with maternal immune cells, may have a 'tolerogenic' function in heart, kidney, and liver transplantation, where HLA-G expression is associated with graft survival. However, the role of HLA-G in lung transplant survival has never been studied, and the relationship between HLA-G genotype and expression of HLA protein of the transplanted lung and host in the development of BOS is completely unknown. The airway mucosa is uniquely sited to mediate the tolerance of the transplanted lung as it represents a major site of interaction between the allograft and the external environment. HLA-G expression by the mucosa may mediate local and circulating immune cells in lung and thus modulate the response to infection and rejection. We propose that both circulating HLA-G and HLA-G expressed in the transplanted lung help to protect the allograft from rejection. We further propose that HLA-G genotype in both donor and host influence levels of HLA-G expression. To address this paradigm we propose the following specific aims: Aim #1. Loss of circulating sHLA-G, and/or loss of HLA-G in the allograft, is associated with clinical symptoms of rejection in patients following lung transplantation. We hypothesize that circulating HLA-G can be detected in patients after lung transplantation, that low levels are associated with greater number of acute rejection episodes in the first year, and that decreased levels of HLA-G pre-date the onset of rejection. We also hypothesize that the airway epithelium in situ and in culture express HLA-G. Aim #2. Levels of expression of circulating HLA-G, and HLA-G in the allograft, depend upon the genotype of the host and the donor, respectively. We hypothesize that HLA-G genotype influences peripheral levels of sHLA-G prior to lung transplant, that the genotype of both the allograft and of the recipient contribute to concentrations of circulating HLA-G, and that genotypes associated with a low expression of HLA-G will be associated with a higher risk for rejection. Understanding the expression of HLA-G in lung transplant patients and the genetic determinants of expression may translate into an earlier, more certain diagnosis of BOS and lead to be better understanding of immune tolerance in lung transplantation. RELEVANCE: Lung transplantation is a life-saving option for selected patients with end-stage lung disease, but rejection of the new lung limits long-term survival. A potent regulator of the immune system, HLA-G, may have a role in protecting the transplanted lung from the host immune system. We propose that HLA-G in the blood and in the new lung of the transplant patient help to protect the allograft from rejection: if true, our application will lead the way for future, large-scale clinical trials that will determine the usefulness of HLA-G as a marker for transplant rejection and perhaps as a life-saving therapy for transplant patients.