Role of epithelial HLA-G in lung transplantation

上皮细胞HLA-G在肺移植中的作用

• 批准号: 7706797
• 负责人: STEVEN R WHITE
• 金额: $ 19.5万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-22 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7706797
• 关键词: Acute; Address; Allografting; Blood; Bronchiolitis Obliterans; Cells; Chronic; Clinical; Clinical Trials; Development; Diagnosis; Environment; Epithelial; Future; Genetic Determinism; Genotype; Graft Rejection; Graft Survival; HLA G antigen; Heart; Immune; Immune Tolerance; Immune system; Immunosuppressive Agents; In Situ; Infection; Kidney; Lead; Life; Lung; Lung Transplantation; Lung diseases; Mediating; Mucous Membrane; Pathogenesis; Patients; Peripheral; Placenta; Planet Mars; Proteins; Risk; Role; Site; Staging; Symptoms; Syndrome; Translating; Transplant Recipients; Transplantation; airway epithelium; clinical Diagnosis; fetus cell; high risk; liver transplantation; pulmonary function; response; success

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.

描述（由申请人提供）：对于选定的终末期肺部疾病的患者，肺移植是挽救生命的选择。慢性同种异体移植排斥（支气管炎闭塞性综合征或BOS）是长期生存的主要局限性，但其发病机理却鲜为人知，包括有效的免疫抑制剂在内的当前疗法在很大程度上是无效的。 BOS的诊断目前取决于临床识别和肺功能下降。这些标记可能只有在BOS建立后才表现出变化，并且在临床诊断中缺乏精度会导致治疗不足或对免疫抑制剂的治疗不当，从而使患者暴露于致命感染的风险。最初在胎盘的胎儿细胞中发现与母体免疫细胞相互作用的非古典HLA I类HLA-G可能在心脏，肾脏和肝移植中具有“耐受性”功能，其中HLA-G表达与移植物存活有关。然而，从未研究过HLA-G在肺移植生存中的作用，而移植肺和宿主在BOS发展中HLA-G基因型与HLA蛋白的表达之间的关系是完全未知的。气道粘膜是独特的，以介导移植肺的耐受性，因为它代表了同种异体移植与外部环境之间的主要相互作用。粘膜的HLA-G表达可能介导肺中的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，在移植的肺中表达的循环HLA-G和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，供体和宿主在HLA-G表达的水平中均具有HLA-G基因型。为了解决此范式，我们提出以下特定目的：目标＃1。同种异体移植中循环SHLA-G和/或HLA-G损失的丧失与肺移植后患者的临床排斥症状有关。我们假设可以在肺移植后患者中检测到循环HLA-G，第一年中低水平与急性排斥的发作数量更多，并且HLA-G的降低水平降低了预排斥的发作。我们还假设气道上皮原位和文化表达HLA-G。目标＃2。同种异体移植中循环HLA-G和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基因型会在肺移植之前影响SHLA-G的外周种水平，同种异体移植物和受体的基因型均导致循环HLA-G的浓度，而与HLA-G表达低的我们的基因型将与拒绝率更高的风险相关。了解HLA-G在肺移植患者中的表达以及表达的遗传决定因素可能会转化为早期，更确定的BOS诊断，并使人们更好地了解肺移植中的免疫耐受性。 相关性：对于选定的终末期肺部疾病的患者而言，肺移植是一种挽救生命的选择，但对新肺部的排斥限制了长期生存。免疫系统HLA-G的有效调节剂可能在保护移植的肺免受宿主免疫系统中起作用。我们提出，血液中的HLA-G在移植患者的新肺中有助于保护同种异体移植物：如果是的，则我们的应用将为未来的大规模临床试验带来途径，这将确定HLA-G作为移植患者的生命疗法的标记，以确定HLA-G的有用性。