Prof. Univ. Dr. Iulia Popescu
Allergy and Critical Care Division, Department Medicine, University of Pittsburgh, Pittsburgh, PA
Short Telomere – Short CMV Immunity in IPF Lung Transplant
Authors: Iulia Popescu, Joseph Pilewski, Yangze Zhang, Carlo Iasella, Mary Armanios, John F. McDyer
RATIONALE: Cytomegalovirus (CMV)-related morbidities remain one of the most common complications after lung transplantation and have been linked to allograft dysfunction, but the factors that predict high risk for CMV complications and effective immunity are incompletely understood.
OBJECTIVES: To determine if short telomeres in idiopathic pulmonary fibrosis (IPF) lung transplant recipients (LTRs) predict the risk for CMV-specific T-cell immunity and viral control.
METHODS: We studied IPF-LTRs (n = 42) and age-matched non-IPF-LTRs (n = 42) and assessed CMV outcomes. We measured lymphocyte telomere length and DNA sequencing, and assessed CMV-specific T-cell immunity in LTRs at high risk for CMV events, using flow cytometry and fluorescence in situ hybridization.
RESULTS: We identified a high prevalence of relapsing CMV viremia in IPF-LTRs compared with non-IPF-LTRs (69% vs. 31%; odds ratio, 4.98; 95% confidence interval, 1.95-12.50; P < 0.001). Within this subset, IPF-LTRs who had short telomeres had the highest risk of CMV complications (P < 0.01) including relapsing-viremia episodes, end-organ disease, and CMV resistance to therapy, as well as shorter time to viremia versus age-matched non-IPF control subjects (P < 0.001). The short telomere defect in IPF-LTRs was associated with significantly impaired CMV-specific proliferative responses, T-cell effector functions, and induction of the major type-1 transcription factor T-bet (T-box 21;TBX21).
CONCLUSIONS: Because the short telomere defect has been linked to the pathogenesis of IPF in some cases, our data indicate that impaired CMV immunity may be a systemic manifestation of telomere-mediated disease in these patients. Identifying this high-risk subset of LTRs has implications for risk assessment, management, and potential strategies for averting post-transplant CMV morbidities.
I am a Research Assistant Professor in the Division of Pulmonary, Allergy, and Critical Care Medicine at the University of Pittsburgh, and I have significant experience in transplant research in basic immunology with a focus on mechanisms of CMV-specific lung mucosal/systemic immunity and viral control, as well on EBV, showing the important role for the Type-1 transcription factor T-bet and Eomes as well other immune markers. I also have experience in studying T cell mechanisms of allograft rejection/tolerance in lung transplantation. I am the Co-PI on a U01 award (AI125050) to perform a novel clinical trial to perform tandem lung and bone marrow transplantation in select individuals with primary immunodeficiencies and end-stage lung disease, and to perform mechanistic pathogen-specific and alloimmune tolerance studies in these study participants. I am also a Co-PI on an R01 award HL133184-01, “Role of F-box Proteins in Lung Transplantation.” In my study I’ve focused in viral mucosal immunology, I am the also Co-PI on U01HL121814, “Immune Mechanisms of HIV-associated COPD. In addition, I am the Co-PI in another lung transplant research effort focused on novel drug development for antibody-mediated lung transplant rejection (Amgen). I am the University of Pittsburgh site Co-PI for the R01, “Clinical Risk Factors in Primary Graft Dysfunction” (HL087115). I am proficient in measuring lung mucosal and systemic viral-specific and allospecific multifunctional T cell immunity and phenotyping in lung transplant recipients. I have helped in the establishment of an extensive lung transplant tissue biorepository/registry (BREATHE-LT) that collects and stores BAL fluid/cells, blood for plasma/PBMC, bronchial brushes, along with a clinical research database for phenotyping lung transplant recipients and assessing outcomes for translational studies. I am also working as a Co-PI on a current CFF award, “Molecular and Clinical Endotypes in Chronic Lung Allograft Dysfunction” in which RNA sequence analysis of the airway transcriptome and proteomics in ongoing studies in the mechanisms of CLAD. Finally, we have recently reported on the impact of short telomeres in pulmonary fibrosis lung transplant recipients who demonstrate increased CMV complications and impaired viral immunity. Pertinent to this proposal I also have significant experience assessing alloimmunity, using flow cytometry, in addition to viral immunity, and evaluate the phenotype of T cells, proliferation and effector multifunction to measure inflammatory responses, that makes me suited to serve as PI on this Stuart K. Patrick grant.
Positions and Employment
2014-pres. Research Assistant Professor, Pulmonary, Allergy and Critical Care Division, Department Medicine, University of Pittsburgh, Pittsburgh, PA
2012-2014 Research Associate/Manager Flow Cytometry Core, Pulmonary, Allergy and Critical Care Division, Department Medicine, University of Pittsburgh, Pittsburgh, PA
2010-2011 Senior Scientist/Technical Application Specialist, Cellular Technology Limited, Shaker Heights, OH
2006-2010 Faculty Research Instructor, Dept of Surgery Thomas E. Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, PA
2001-2006 Postdoctoral Research Associate, Dept of Surgery Thomas E. Starzl Transplantation Institute, University of Pittsburgh, Pittsburgh, PA
2000-2001 Research Scientist, Dept. of Cellular Immunology and Signal Transduction, Center of Immunology, Institute of Virology Bucharest, Romania
1997- 2000 Junior Research Scientist, Department Clinical Immunology, Center for Immunology, Bucharest, Romania
1997 3 months-Visiting Research PhD, Doctoral Scientist, Cancer Institute, University of Pittsburgh, Pittsburgh, PA.
1994-1997 Research Associate – Dept. of Cellular Immunology and Signal Transduction, Center of Immunology, Institute of Virology, Bucharest, Romania
1991-1994 Resident Scientist- Department Clinical Immunology, Center for Immunology, Bucharest, Romania
1986-1991 Research Assistant, Department of Interferon Research / Immune-modulators, V. Babes Institute, Bucharest, Romania
Member – American Society of Transplantation (AST) 2006-present
Member – American Immunology Association (AIA) 2007-present
Member – European Association for Cancer Research (EACR) 1998-present
Member – Federation of European Biochemical Societies (FEBS) 1990-present
Member – Romanian Society of Immunology (SNI) 1986-present
Member – International Society of Heart and Lung Transplantation 2019-present