Dataset Information

NK and CD8+ T cell phenotypes predict onset and control of CMV viremia after kidney transplant.

ABSTRACT: CMV causes mostly asymptomatic but lifelong infection. Primary infection or reactivation in immunocompromised individuals can be life-threatening. CMV viremia often occurs in solid organ transplant recipients and associates with decreased graft survival and higher mortality. Furthering understanding of impaired immunity that allows CMV reactivation is critical to guiding antiviral therapy and examining the effect of CMV on solid organ transplant outcomes. This study characterized longitudinal immune responses to CMV in 31 kidney transplant recipients with CMV viremia and matched, nonviremic recipients. Recipients were sampled 3 and 12 months after transplant, with additional samples 1 week and 1 month after viremia. PBMCs were stained for NK and T cell markers. PBMC transcriptomes were characterized by RNA-Seq. Plasma proteins were quantified by Luminex. CD8+ T cell transcriptomes were characterized by single-cell RNA-Seq. Before viremia, patients had high levels of IL-15 with concurrent expansion of immature CD56bright NK cells. After viremia, mature CD56dim NK cells and CD28-CD8+ T cells upregulating inhibitory and NK-associated receptors were expanded. Memory NK cells and NK-like CD28-CD8+ T cells were associated with control of viremia. These findings suggest that signatures of innate activation may be prognostic for CMV reactivation after transplant, while CD8+ T cell functionality is critical for effective control of CMV.

SUBMITTER: Pickering H

PROVIDER: S-EPMC8663544 | biostudies-literature | 2021 Nov

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

NK and CD8+ T cell phenotypes predict onset and control of CMV viremia after kidney transplant.

Pickering Harry H Sen Subha S Arakawa-Hoyt Janice J Ishiyama Kenichi K Sun Yumeng Y Parmar Rajesh R Ahn Richard S RS Sunga Gemalene G Llamas Megan M Hoffmann Alexander A Deng Mario M Bunnapradist Suphamai S Schaenman Joanna M JM Gjertson David W DW Rossetti Maura M Lanier Lewis L LL Reed Elaine F EF

JCI insight 20211108 21

CMV causes mostly asymptomatic but lifelong infection. Primary infection or reactivation in immunocompromised individuals can be life-threatening. CMV viremia often occurs in solid organ transplant recipients and associates with decreased graft survival and higher mortality. Furthering understanding of impaired immunity that allows CMV reactivation is critical to guiding antiviral therapy and examining the effect of CMV on solid organ transplant outcomes. This study characterized longitudinal im ...[more]

PMID: 34609965

Similar Datasets

Project description:IntroductionCytomegalovirus (CMV) is the most frequent infectious complication following solid organ transplantation. Torque teno viruses (TTV) viremia has been proposed as a biomarker of functional immunity in the management of kidney transplant recipients (KTR). The QuantiFERON®-CMV (QF-CMV) is a commercially available assay that allows the assessment of CD8+ T-cell responses in routine diagnostic laboratories.MethodsIn a prospective national multicenter cohort of 64 CMV-seropositive (R+) KTR, we analyzed the value of TTV load and the two markers of the QF-CMV assay [QF-Ag (CMV-specific T-cell responses) and QF-Mg (overall T-cell responses)], alone and in combination, in prediction of CMV reactivation (≥3 log10 IU/ ml) in the first post-transplant year. We compared previously published cut-offs and specific cut-offs optimized from ROC curves for our population.ResultsUsing the conventional cut-off (3.45 log10 copies/ml), TTV load at D0 [inclusion visit on the day of transplantation before induction (D0)], or at M1 (1-month post-transplant visit) perform better in predicting CMV viremia control than CMV reactivation. Survival analyses suggest a better performance of our optimized TTV cut-offs (3.78 log10 copies/ml at D0 and 4.23 log10 copies/ml at M1) for risk stratification of CMV reactivation in our R+ KTR cohort. The QF-CMV (QF-Ag = 0.2 IU/ml, and QF-Mg = 0.5 IU/ml) also appears to better predict CMV viremia control than CMV reactivation. Moreover, survival analyses suggest that the QF-Mg would perform better than the QF-Ag in stratifying the risk of CMV reactivation. The use of our optimized QF-Mg cut-off (1.27 IU/ml) at M1 further improved risk stratification of CMV reactivation. Using conventional cut-offs, the combination of TTV load and QF-Ag or TTV load and QF-Mg did not improve prediction of CMV viremia control compared to separate analysis of each marker but resulted in an increase of positive predictive values. The use of our cut-offs slightly improved risk prediction of CMV reactivation.ConclusionThe combination of TTV load and QF-Ag or TTV load and QF-Mg could be useful in stratifying the risk of CMV reactivation in R+ KTR during the first post-transplant year and thereby have an impact on the duration of prophylaxis in these patients.Clinical trial registrationClinicalTrials.gov registry, identifier NCT02064699.

Project description:Background: Although the clinical fingerprints of the BK virus (BKV) infection in kidney transplant recipients (KTRs) has been well documented, the systemic biological machinery involved in this complication is still poorly recognized. Proteomics analysis of urinary extracellular vesicles (EVs) can allow us to better address this knowledge gap. Methods: Twenty-nine adult KTRs with normal allograft function affected by BKV infection (15 with only viremia, 14 with viruria and viremia) and 15 controls (CTR) were enrolled and randomly divided in a training cohort (12 BKV and 6 CTR) used for the mass spectrometry analysis of the EVs protein content and a testing cohort(17 BKV and 9 CTR) used for the biological validation of the proteomic results by ELISA. Results: Mass spectrometry analysis revealed a large protein enrichment (more than 1500) in urinary EVs of BKV patients and controls. Pathway analysis by GSEA revealed that several biological gene ontologies (including immunity, complement activation, renal fibrosis, tubular diseases, epithelial to mesenchymal transition) were able to discriminate BKV versus CTR. Kinase was the only gene ontology annotation term negatively enriched in BKV (with SLK being the most down-regulated protein in BKV). Statistical analysis, then, identified a core panel of 70 proteins (including DNASE2, F12, AGT, CTSH, C4A, C7, FABP4 and BPNT1) able to discriminate the two study groups. Instead, although a set of proteins were able to differentiate patients with BKV viruria from those with both viremia-viruria, the urinary proteomic profile of these patients resulted quite similar between the two sub-groups. ELISA for SLK and ELISA for BPNT1 and DNASE2 validated proteomics results. Conclusions: Our study demonstrated that BK virus infection is able to significantly modify the urinary EVs proteomic profile of KTRs also in a very early stage of the disease (when patients still have normal allograft function and only BK viruria) suggesting, whether possible, to start an early preventive therapeutic approach to minimize the risk of the disease progression. Moreover, some 3 of our identified proteins could be employed in future as early urinary biomarkers and/or new therapeutic targets.

Project description:BackgroundGlucose metabolism links closely to cholesterol metabolism. Posttransplant diabetes mellitus (PTDM) adversely affects posttransplant outcomes, but its risk factors in relation to cholesterol metabolism have not been fully delineated. The apolipoprotein B/A1 (Apo B/A1) ratio, which is associated with insulin resistance, has not been evaluated in kidney transplant recipients as a risk factor for PTDM.ObjectiveThe objective of this study was to determine whether serum apolipoprotein profiles predict late PTDM, defined as a new onset diabetes occurring greater than 3 months posttransplant.DesignRetrospective chart review of a prevalent population of kidney transplant recipients.SettingLarge transplant center in Ontario, Canada.PatientsWe identified 1104 previously nondiabetic adults who received a kidney transplant between January 1, 1998, and December 1, 2015, and were followed at 1 transplant center.MeasurementsRecipients provided testing for serum apolipoprotein B (Apo B) and apolipoprotein A1 (Apo A1) concentrations from 2010, either at 3 months posttransplant for new transplant recipients or the next clinic visit for prevalent recipients. Late PTDM defined using Canadian Diabetes Association criteria as occurring ≥3 months posttransplant was recorded until May 1, 2016.MethodsAll analyses were conducted with R, version 3.4.0 (The R Foundation for Statistical Computing). Comparisons were made using Student t test, Fisher exact test or chi-square test, Kaplan-Meier methodology with the logrank test, or Cox proportional hazards analysis as appropriate. Covariates for the multivariate Cox proportional hazards models of PTDM as the outcome variable were selected based on significance of the univariate associations and biological plausibility.ResultsThere were 53 incident late PTDM cases, or 1.71 cases per 100 patient-years. Incident late PTDM differed between the highest and lowest quartiles for Apo B/A1 ratio, 2.47 per 100 patient-years vs 0.88 per 100 patient-years (P = .005 for difference). In multiple Cox regression analysis, first measured serum Apo B/A1 concentration better predicted subsequent PTDM than low-density lipoprotein cholesterol (LDL-C; hazard ratio [HR] = 7.80 per unit increase, P = .039 vs HR = 1.05 per unit increase, P = .774). Non-high-density lipoprotein cholesterol (HDL-C) concentrations also did not predict PTDM (P = .136). By contrast to Apo B, Apo A1 was protective against PTDM in statin users (HR = 0.17 per unit increase, P = .016).LimitationsPosttransplant diabetes mellitus cases occurring before apolipoprotein testing was implemented were not included in the analysis.ConclusionsApolipoproteins B and A1 better predict late PTDM than conventional markers of cholesterol metabolism.

Dataset Information

NK and CD8+ T cell phenotypes predict onset and control of CMV viremia after kidney transplant.

Publications

NK and CD8+ T cell phenotypes predict onset and control of CMV viremia after kidney transplant.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets