The Role of Telomeres in Lung Transplant Recipient Immunity and Outcomes

点击翻译按钮获取中文摘要

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.