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1.
Am J Transplant ; 20(5): 1439-1446, 2020 05.
Article in English | MEDLINE | ID: mdl-31874120

ABSTRACT

Epstein-Barr virus (EBV)-associated posttransplant lymphoproliferative disorder (EBV-PTLD) is a serious complication in lung transplant recipients (LTRs) associated with significant mortality. We performed a single-center retrospective study to evaluate the risks for PTLD in LTRs over a 7-year period. Of 611 evaluable LTRs, we identified 28 cases of PTLD, with an incidence of 4.6%. Kaplan-Meier analysis showed a decreased freedom from PTLD in idiopathic pulmonary fibrosis (IPF)-LTRs (P < .02). Using a multivariable Cox proportional hazards model, we found IPF (hazard ratio [HR] 3.51, 95% confidence interval [CI] 1.33-8.21, P = .01) and alemtuzumab induction therapy (HR 2.73, 95% CI 1.10-6.74, P = .03) as risk factors for PTLD, compared to EBV mismatch (HR: 34.43, 95% CI 15.57-76.09, P < .0001). Early PTLD (first year) was associated with alemtuzumab use (P = .04), whereas IPF was a predictor for late PTLD (after first year) (P = .002), after controlling for age and sex. Kaplan-Meier analysis revealed a shorter time to death from PTLD in IPF LTRs compared to other patients (P = .04). The use of alemtuzumab in EBV mismatch was found to particularly increase PTLD risk. Together, our findings identify IPF LTRs as a susceptible population for PTLD. Further studies are required to understand the mechanisms driving PTLD in IPF LTRs and develop strategies to mitigate risk.


Subject(s)
Epstein-Barr Virus Infections , Idiopathic Pulmonary Fibrosis , Lymphoproliferative Disorders , Epstein-Barr Virus Infections/etiology , Herpesvirus 4, Human , Humans , Idiopathic Pulmonary Fibrosis/etiology , Lung , Lymphoproliferative Disorders/etiology , Retrospective Studies , Risk Factors , Transplant Recipients
2.
J Immunol ; 203(8): 2063-2075, 2019 10 15.
Article in English | MEDLINE | ID: mdl-31554693

ABSTRACT

CMV remains an important opportunistic pathogen in high-risk lung transplant recipients. We characterized the phenotype and function of CD8+ T cells from acute/primary into chronic CMV infection in 23 (donor+/recipient-; D+R-) lung transplant recipients and found rapid induction of both KLRG1+ and/or CD57+ CMV-specific CD8+ T cells with unexpected coexpression of CD27. These cells demonstrated maturation from an acute effector T cell (TAEFF) to an effector memory T cell (TEM) phenotype with progressive enrichment of KLRG1+CD57+CD27- cells into memory. CMV-specific KLRG1+ TAEFF were capable of in vitro proliferation that diminished upon acquisition of CD57, whereas only KLRG1+ expression correlated with T-bet expression and effector function. In contrast to blood TAEFF, lung mucosal TAEFF demonstrated reduced KLRG1/T-bet expression but similar CD57 levels. Additionally, increased KLRG1+TAEFF were associated with early immune viral control following primary infection. To our knowledge, our findings provide new insights into the roles of KLRG1 and CD57 expression in human T cells, forming the basis for a refined model of CD8+ T cell differentiation during CMV infection.


Subject(s)
Cytomegalovirus Infections/immunology , Cytomegalovirus Infections/virology , Cytomegalovirus/immunology , Lectins, C-Type/immunology , Receptors, Immunologic/immunology , Adult , CD57 Antigens/immunology , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/virology , Cell Differentiation/immunology , Cell Proliferation , Female , Humans , Male , Middle Aged , Young Adult
3.
Am J Respir Crit Care Med ; 199(3): 362-376, 2019 02 01.
Article in English | MEDLINE | ID: mdl-30088779

ABSTRACT

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. MEASUREMENTS AND MAIN 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.


Subject(s)
Cytomegalovirus Infections/complications , Cytomegalovirus Infections/immunology , Idiopathic Pulmonary Fibrosis/complications , Lung Transplantation , Telomere/immunology , Transplant Recipients/statistics & numerical data , Adult , Aged , Cytomegalovirus/immunology , Female , Humans , Idiopathic Pulmonary Fibrosis/immunology , Immunity , Male , Middle Aged
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