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）是长期生存的主要限制，但其发病机制尚不清楚，目前的治疗方法，包括强效免疫抑制剂，在很大程度上是无效的。目前对BOS的诊断依赖于临床识别和肺功能下降。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使用免疫抑制剂治疗不当，使患者面临致命感染的风险。HLA- g是一种非经典的HLA- I类分子，首次在胎盘的胎儿细胞中发现，它与母体免疫细胞相互作用，可能在心脏、肾脏和肝脏移植中具有“耐受性”功能，其中HLA- g的表达与移植物存活有关。然而，HLA- g在肺移植存活中的作用从未被研究过，HLA- g基因型与移植肺和宿主HLA蛋白表达在BOS发生中的关系也完全未知。气道黏膜是介导移植肺耐受的独特部位，因为它是同种异体移植物与外部环境相互作用的主要部位。HLA-G在肺粘膜的表达可能介导局部和循环免疫细胞，从而调节对感染和排斥的反应。我们提出循环HLA-G和移植肺中表达的HLA-G有助于保护同种异体移植物免受排斥。我们进一步提出，供体和宿主的HLA-G基因型都影响HLA-G的表达水平。为了解决这个范例，我们提出以下具体目标：目标#1。循环sHLA-G的丢失和/或同种异体移植物中HLA-G的丢失与肺移植后患者的临床排斥症状有关。我们假设循环HLA-G可以在肺移植后的患者中检测到，低水平的HLA-G与第一年更多的急性排斥反应发作有关，并且HLA-G水平的降低早于排斥反应的发生。我们也假设原位和培养的气道上皮表达HLA-G。目标# 2。循环HLA-G和HLA-G在同种异体移植物中的表达水平分别取决于宿主和供体的基因型。我们假设HLA-G基因型会影响肺移植前外周血sHLA-G水平，同种异体移植物和受体的基因型都会影响循环HLA-G浓度，HLA-G低表达的基因型会导致更高的排斥风险。了解HLA-G在肺移植患者中的表达及其表达的遗传决定因素可能有助于更早、更明确地诊断BOS，并有助于更好地了解肺移植患者的免疫耐受。

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.