Role of epithelial HLA-G in lung transplantation

描述（由申请人提供）：肺移植是终末期肺病患者的一种挽救生命的选择。慢性同种异体移植排斥反应（闭塞性细支气管炎综合征，或BOS）是长期生存的主要限制因素，但其发病机制知之甚少，目前的治疗，包括有效的免疫抑制剂，在很大程度上是无效的。BOS的诊断目前依赖于临床识别和肺功能下降。这些标志物可能仅在BOS建立后才出现变化，临床诊断缺乏精确性导致治疗不足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HLA I类分子，HLA-G，首先在胎盘的胎儿细胞中发现，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“致耐受性”功能，其中HLA-G表达与移植物存活相关。然而，HLA-G在肺移植存活中的作用尚未被研究，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。气道粘膜是唯一介导移植肺耐受的部位，因为它代表了同种异体移植物与外部环境之间相互作用的主要部位。HLA-G在肺粘膜的表达可能介导肺局部和循环免疫细胞，从而调节对感染和排斥的反应。我们认为，循环中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反应。我们进一步提出供体和宿主的HLA-G基因型影响HLA-G表达水平。为了解决这个问题，我们提出了以下具体目标：目标#1。循环中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排斥反应的临床症状相关。我们假设肺移植后患者的循环中可以检测到HLA-G，低水平与第一年发生的急性排斥反应次数增加有关，HLA-G水平的降低早于排斥反应的发生。我们还假设原位和培养的气道上皮表达HLA-G。目标2。循环HLA-G和同种异体移植物中HLA-G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均影响循环HLA-G浓度，与HLA-G低表达相关的基因型与较高的排斥风险相关。了解肺移植患者中HLA-G的表达以及表达的遗传决定因素可能有助于更早、更确定地诊断BOS，并有助于更好地了解肺移植中的免疫耐受。 相关性：肺移植是终末期肺病患者的一种挽救生命的选择，但新肺的排斥反应限制了长期生存。免疫系统的有效调节剂HLA-G可能在保护移植肺免受宿主免疫系统的影响方面发挥作用。我们建议移植患者血液和新肺中的HLA-G有助于保护同种异体移植物免受排斥反应：如果属实，我们的应用将为未来的大规模临床试验铺平道路，这些试验将确定HLA-G作为移植排斥反应标志物的有用性，并可能作为移植患者的挽救生命的治疗方法。

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.