The Role of Telomeres in Lung Transplant Recipient Immunity and Outcomes

端粒在肺移植受者免疫和结果中的作用

• 批准号: 10561968
• 负责人: Jonathan K. Alder
• 金额: $ 72.35万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-03-05 至 2028-02-29
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10561968
• 关键词: Acute; Age; Allografting; Biological; Bronchoalveolar Lavage; Brush Cell; CD4 Positive T Lymphocytes; CD8B1 gene; Caring; Cell Aging; Cell physiology; Chronic; Clinical; Complex; Complication; Cytomegalovirus; Cytomegalovirus Infections; Data; Defect; Disease; Flow Cytometry; Functional disorder; Gene Expression Profile; Genes; Genetic; Germ-Line Mutation; Host Defense; Human Herpesvirus 4; Immune; Immune response; Immune system; Immunity; Immunologics; Immunosuppression; Impairment; In Vitro; Individual; Knowledge; Length; Lung; Lung Transplantation; Lung diseases; Lymphoproliferative Disorders; Measures; Mediating; Molecular; Mutation; North America; Outcome; Pathogenicity; Patients; Peripheral Blood Mononuclear Cell; Phenotype; Predisposition; Publishing; Pulmonary Fibrosis; Reporting; Risk; Role; Sampling; Syndrome; T-Lymphocyte; Telomere Maintenance; Telomere Maintenance Gene; Testing; Therapeutic; Transplant Recipients; Transplantation; Universities; Viral; Virus Diseases; Work; adaptive immunity; allograft rejection; cohort; genetic variant; genome sequencing; idiopathic pulmonary fibrosis; immunosenescence; improved; insight; lung allograft; post-transplant; rare variant; response; senescence; single-cell RNA sequencing; telomere; transcriptome; transcriptome sequencing; whole genome

Project Summary Lung transplantation (LTx) is the only therapeutic option for patients with end-stage lung disease and idiopathic pulmonary fibrosis (IPF) is the most common indication in North America. However, IPF lung transplant recipients (IPF-LTRs) have worse transplant survival compared to all other lung diseases. Mutations in the genes responsible for telomere maintenance are the most common identifiable cause of IPF and our group recently showed that lung transplantation enriches for patients with telomere-mediated disease with as many as a quarter of patients having an identifiable rare variant. Patients with defects in telomere-maintenance genes have an array of immunologic abnormalities that render them susceptible to viral infections. Despite having a weakened immune system, these patients have been reported to reject donor lungs at similar or faster rates than individuals without telomere-mediated disease. The mechanism responsible for this phenomenon are unknown. Based on our preliminary data, we hypothesize that lung transplantation unmasks a complex syndrome that impacts viral host defense, immunosuppression tolerance and allograft rejection. Further, we hypothesize that impaired adaptive immunity is exacerbated by Cytomegalovirus infection by augmenting immunosenescence, however alloimmune and other immune mechanisms can offset and facilitate lung rejection outcomes in transplant recipients with short telomeres. We have divided our approach into three related and synergistic aims. In Aim 1, we examine the consequences of primary CMV infection in patients with telomere-mediate disease and test if two hits, telomere dysfunction and CMV infection, cooperate to drive immune senescence. In Aim 2, we explore the mechanisms that are responsible for lung rejection in individuals with weakened immune systems. Finally, in Aim 3, we test if our recent findings from the University of Pittsburgh can be replicated and extended in a multi- center group of patients from the Lung Transplant Outcomes Group and examine keep outcomes following lung transplantation when stratified by genetic findings and telomere length. We expect that these studies will help improve care and outcomes in patients with telomere-mediated disease.

项目概要 肺移植（LTx）是终末期肺病和特发性患者的唯一治疗选择 肺纤维化（IPF）是北美最常见的适应症。然而，IPF 肺移植受者 与所有其他肺部疾病相比，（IPF-LTR）的移植存活率更差。基因突变 负责端粒维护的是 IPF 最常见的可识别原因，我们小组最近 研究表明，肺移植可以使患有端粒介导疾病的患者增加四分之一 具有可识别的罕见变异的患者。端粒维持基因缺陷的患者 一系列免疫异常使他们容易受到病毒感染。尽管实力较弱 据报道，这些患者的免疫系统对供体肺部的排斥率与个体相似或更快 无端粒介导的疾病。造成这种现象的机制尚不清楚。基于 根据我们的初步数据，我们假设肺移植揭示了一种影响病毒的复杂综合征 宿主防御、免疫抑制耐受和同种异体移植排斥。此外，我们假设受损 然而，巨细胞病毒感染会增强免疫衰老，从而加剧适应性免疫 同种免疫和其他免疫机制可以抵消并促进移植中的肺排斥结果 端粒较短的受体。我们将我们的方法分为三个相关且协同的目标。在目标 1 中， 我们检查了原发性 CMV 感染对端粒介导疾病患者的影响，并测试是否 端粒功能障碍和巨细胞病毒感染这两个打击共同驱动免疫衰老。在目标 2 中，我们探索 导致免疫系统较弱的个体肺部排斥反应的机制。最后， 在目标 3 中，我们测试匹兹堡大学最近的发现是否可以在多个领域进行复制和扩展。 来自肺移植结果组的中心组患者，并检查肺移植后的保留结果 根据遗传发现和端粒长度分层进行移植。我们希望这些研究能够有所帮助 改善端粒介导疾病患者的护理和结果。