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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

基本信息

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
项目类别：
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

项目摘要

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.

项目总结