CMV driven CD8+ T-cell activation is associated with acute rejection in lung transplantation (original) (raw)
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American Journal of Respiratory and Critical Care Medicine, 2016
Rationale: Cytomegalovirus (CMV), which is one of the most common infections after lung transplantation, is associated with chronic lung allograft dysfunction and worse post-transplantation survival. Current approaches for at-risk patients include a fixed duration of antiviral prophylaxis despite the associated cost and side effects. Objectives: We sought to identify a specific immunologic signature that predicted protection from subsequent CMV. Methods: CMV-seropositive lung transplantation recipients were included in the discovery (n = 43) and validation (n = 28) cohorts. Polyfunctional CMV-specific immunity was assessed by stimulating peripheral blood mononuclear cells with CMV pp65 or IE-1 peptide pools and then by measuring T-cell expression of CD107a, IFN-g, tumor necrosis factor-a (TNF-a), and IL-2. Recipients were prospectively monitored for subsequent viremia. A Cox proportional hazards regression model that considered cytokine responses individually and in combination was used to create a predictive model for protection from CMV reactivation. This model was then applied to the validation cohort. Measurements and Main Results: Using the discovery cohort, we identified a specific combination of polyfunctional T-cell subsets to pp65 that predicted protection from subsequent CMV viremia (concordance index 0.88 [SE, 0.087]). The model included both protective (CD107a 2 /IFN-g 1 /IL-2 1 /TNF-a 1 CD4 1 T cells, CD107a 2 /IFN-g 1 /IL-2 1 /TNF-a 1 CD8 1 T cells) and detrimental (CD107a 1 /IFN-g 1 /IL-2 2 /TNF-a 2 CD8 1 T cells) subsets. The model was robust in the validation cohort (concordance index 0.81 [SE, 0.103]). Conclusions: We identified and validated a specific T-cell polyfunctional response to CMV antigen stimulation that provides a clinically useful prediction of subsequent cytomegalovirus risk. This novel diagnostic approach could inform the optimal duration of individual prophylaxis.
American Journal of Transplantation, 2005
Patients after kidney, heart and lung transplantation differ in their immunosuppressive drug regimens and in susceptibility to infectious complications with cytomegalovirus (CMV). In this study, CMV-specific T-cell responses were characterized in long-term transplant recipients and associated with the frequency of infectious complications. CMV-reactive CD4 T cells from 50 healthy controls, 68 renal, 14 heart and 24 lung transplant recipients were flow cytometrically quantified by the induction of cytokines after specific stimulation. Moreover, the immunosuppressive effect of calcineurin inhibitors on specific T-cell reactivity was quantified in vitro and compared with responses in vivo. Median CMV-specific T-cell frequencies in long-term renal (1.48%; range 0.06-17.26%) and heart transplant recipients (0.90%; 0.13-12.49%) did not differ from controls (1.82%; 0.26-21.00%). In contrast, CMV-specific T-cell levels were significantly lower in lung transplant recipients (0.50%; <0.05-4.98%) and showed a significant correlation with the frequency of infectious episodes (r = −0.57, p = 0.005). The differences within the groups were associated with increasing dosages of immunosuppressive drugs, as exemplified for calcineurin inhibitors that dose dependently reduced specific T-cell reactivity in vitro. In conclusion, monitoring CMV-specific CD4 T cells may serve as a measure for long-term disease susceptibility and may contribute to an improved management of CMV complications after lung transplantation.
Clinical significance of CMV-specific T helper responses in lung transplant recipients
Human Immunology, 1998
Background. Cytomegalovirus (CMV) disease continues to be a major problem for lung transplant patients who generate an inefficient immune response to control this viral infection. Both T helper and cytotoxic T cells are thought to play an important role in prevention and control of CMV disease. We investigated the clinical significance of CMV-specific memory responses in lung transplant recipients. Method. Peripheral blood samples (140) were collected from 99 lung transplant recipients. Patients were grouped according to their pre-transplant CMV serological status as recipient/donor (RϪ/Dϩ, 25 patients), 28 Rϩ/Dϩ patients, 35 Rϩ/DϪ patients and 11 RϪ/DϪ patients. Memory responses to CMV whole antigen, 5 CMV proteins, and tetanus toxoid (TT) were measured in a 6-day proliferative assay. Results were expressed as the stimulation index (SI ϭ experimental cpm/background cpm), and were considered positive if the SI was Ͼ3 and the cpm values were over 1,000. Results. The frequency of positive CMV memory responses was similar in three groups: 64% for RϪ/Dϩ, 63% for Rϩ/Dϩ and 56% for Rϩ/DϪ except for RϪ/DϪ (21%). The memory response to TT was similar for all four groups (70% of samples were positive). The level of responsiveness to individual CMV proteins was much higher in Rϩ/Dϩ group (65%) than the other two
Therapeutic Advances in Respiratory Disease, 2020
Background: Immune responses, both cellular and humoral, against cytomegalovirus (CMV) are used to predict CMV manifestations in solid organ recipients. The aim of this study is to evaluate CMV enzyme-linked immunospot (ELISPOT) assay and serology during CMV infections, their concordance and variations after lung transplantation (LTx). Methods: We retrospectively analysed in one year the follow-up data of 43 patients receiving combined CMV prophylaxis with antiviral agents and CMV-specific immunoglobulin G (IgG). CMV infections were investigated by using molecular analyses on both 167 bronchoalveolar lavage and biopsy specimens and 1134 blood samples. Cellular CMV immunity was assessed with specific ELISPOT whereas the humoral one was assessed by quantifying specific immunoglobulins. Results: At the first month after LTx the majority of patients were ELISPOT responders (52.3%) and 30.9% were non-responders. ELISPOT responders had a lower incidence of CMV viremia ( p = 0.047), wherea...
The Journal of Immunology, 2008
Acquisition of T cell responses during primary CMV infection in lung transplant recipients (LTRs) appear critical for host defense and allograft durability, with increased mortality in donor+/recipient− (D+R−) individuals. In 15 D+R− LTRs studied, acute primary CMV infection was characterized by viremia in the presence or absence of pneumonitis, with viral loads higher in the lung airways/allograft compared with the blood. A striking influx of CD8+ T cells into the lung airways/allograft was observed, with inversion of the CD4+:CD8+ T cell ratio. De novo CMV-specific CD8+ effector frequencies in response to pooled peptides of pp65 were strikingly higher in lung mononuclear cells compared with the PBMC and predominated over IE1-specific responses and CD4+ effector responses in both compartments. The frequencies of pp65-specific cytokine responses were significantly higher in lung mononuclear cells compared with PBMC and demonstrated marked contraction with long-term persistence of ef...
2001
Background: Cytomegalovirus (CMV) pneumonitis has been shown to be associated with lymphocytic alveolitis after lung transplantation. In the present study, we investigated a series of bronchoalveolar (BAL) and blood samples, collected in the absence of rejection or acute infectious episodes. in order -1: to evaluate intra-alveolar cell population changes concomitant with CMV replication and -2: to reappraise the value of cell population analysis in the management of patients after lung transplantation.
Association of CMV‐specific T‐cell immunity and risk of CMV infection in lung transplant recipients
Clinical Transplantation, 2021
BackgroundProtecting against CMV infection and maintaining CMV in latent state are largely provided by CMV‐specific T‐cells in lung transplant recipients. The aim of the study was to assess whether a specific T‐cell response is associated with the risk for CMV infection in seronegative patients who are at high risk for delayed CMV infection.MethodsAll CMV‐seronegative recipients (R−) from CMV‐seropositive donors (D+) between January 2018 and April 2019 were included and retrospectively screened for CMV infection before and after assessment of CMV‐specific cell‐mediated immunity.ResultsThirty‐one of the 50 patients (62%) developed early‐onset CMV infection. Lower absolute neutrophil counts were significantly associated with early‐onset CMV infection. Antiviral prophylaxis was ceased after 137.2 ± 42.8 days. CMV‐CMI were measured at a median of 5.5 months after LTx. 19 patients experienced early and late‐onset CMV infection after prophylaxis withdrawal within 15 months post transplant...
Journal of Experimental Medicine, 2005
from CMV disease have not been defined. However, responses to the pp65 protein are believed to play an important role. Here, the proportions of interferon ␥ -producing T cells following ex vivo activation with pools of overlapping peptides representing the pp65 and immediate early (IE)-1 proteins were determined at multiple time points and related to the development of CMV disease in 27 heart and lung transplant recipients. Frequencies of IE-1-specific CD8 T cells above 0.2 and 0.4% at day 0 and 2 wk, respectively, or 0.4% at any time during the first months discriminated patients who did not develop CMV disease from patients at risk, 50-60% of whom developed CMV disease. No similar distinction between risk groups was possible based on pp65-specific CD8 or CD4 T cell responses. Remarkably, CMV disease developed exclusively in patients with a dominant pp65-specific CD8 T cell response. In conclusion, high frequencies of IE-1 but not pp65-specific CD8 T cells correlate with protection from CMV disease. These results have important implications for monitoring T cell responses, adoptive cell therapy, and vaccine design.