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Enhancement of Cytomegalovirus-Specific Cytokine Production after Modulation of the Costimulation in Kidney Transplant Patients.

ABSTRACT: Kidney transplantation is the therapy of choice for patients with end stage renal disease. Due to immunosuppressive treatment, patients are at risk for opportunistic infections. Cytomegalovirus (CMV) reactivation is highly relevant in kidney transplant recipients because it occurs-depending on the serological constellation of the donor and recipient-in more than half of the patients and influences patient outcome. Patients with CMV reactivation show decreased allograft and overall survival. Previous studies could demonstrate that transplant patients often show weak CMV-specific immunity. Besides immunosuppressive treatment, additional mechanisms may reduce CMV-specific immunocompetence such as enhanced negative costimulation. Hence, the aim of this study was to investigate if the function of CMV-specific cells of kidney transplant recipients could be restored by a modulation of costimulatory molecules. To address this question, lymphocytes of kidney transplant patients were stimulated with CMV-specific antigens and incubated with programmed death-ligand 1 (PD-L1), programmed cell death protein 1 (PD-1), or B- and T-lymphocyte attenuator (BTLA) antibodies. Afterwards, the IFN-?, IL-21, and IL-17A production was measured by the ELISpot assay. It could be shown that a blockade of the ligand PD-L1 resulted in an increased CMV-specific IFN-?, IL-21, and IL-17A secretion. The blockade of the receptor PD-1 distinctly enhanced the production of IL-21. BTLA antibodies, however, led only to a marginal increase of CMV-specific IFN-? and of IL-21 production. Experiments in healthy controls could confirm the results of the kidney transplant recipients. Furthermore, they could demonstrate that treatment with the immunosuppressive drug tacrolimus resulted in decreased CMV-specific IFN-? and of IL-21 production. Thus, our study could show for the first time that the blockade of the PD-L1/PD-1 pathway also modulates CMV-specific Th21 and Th17 cell function in kidney transplant recipients. Further studies are mandatory to clarify the role of Th21 and Th17 cells in CMV control of these patients.

SUBMITTER: Dornieden T

PROVIDER: S-EPMC6410444 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Enhancement of Cytomegalovirus-Specific Cytokine Production after Modulation of the Costimulation in Kidney Transplant Patients.

Dornieden Theresa T Wilde Benjamin B Korth Johannes J Werner Kai K Horn Peter A PA Witzke Oliver O Lindemann Monika M

Journal of immunology research 20190225

Kidney transplantation is the therapy of choice for patients with end stage renal disease. Due to immunosuppressive treatment, patients are at risk for opportunistic infections. Cytomegalovirus (CMV) reactivation is highly relevant in kidney transplant recipients because it occurs-depending on the serological constellation of the donor and recipient-in more than half of the patients and influences patient outcome. Patients with CMV reactivation show decreased allograft and overall survival. Prev ...[more]

PMID: 30931336

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Project description:IntroductionOpportunistic viral infections cause extensive morbidity and mortality in kidney transplant recipients (KTRs). Low serum albumin levels before and after transplant have been associated with negative outcomes. However, it is uncertain whether serum albumin levels before transplantation are associated with the risk for post-transplantation opportunistic BK polyomavirus (BKV) or cytomegalovirus (CMV).MethodsWe reviewed all KTRs transplanted at our institution between 1 January 2005 and 31 December 2015 with serum albumin measured within 45 days before transplantation in a retrospective observational cohort study. Selected patients were stratified into 3 groups: normal albuminemia (≥3.5 g/dl), moderate hypoalbuminemia (3.49-2.5 g/dl), and severe hypoalbuminemia (<2.5 g/dl). Patients were observed for post-transplantation BKV or CMV according to standard of care.ResultsWe included 1717 patients in this study; 72.3% had normal serum albumin, 26.3% had moderate hypoalbuminemia, and 1.5% had severe hypoalbuminemia. Moderate and severe hypoalbuminemia incurred a higher risk for BKV compared with normal serum albumin levels in univariable analysis (moderate hypoalbuminemia: hazard ratio [HR] = 1.5; 95% confidence interval [CI], 1.14-1.90; P = .003); severe hypoalbuminemia: HR = 2.15; 95% CI, 1.01-4.56; P = 0.05). Although not significant after multivariable adjustment, there was still 18% increased risk in moderate hypoalbuminemia and 64% in severe hypoalbuminemia for BKV compared with the normal albumin group. Moderate hypoalbuminemia was associated with a higher risk for CMV infection than normal serum albumin levels in multivariable analysis, although it was not statistically significant (HR = 1.15; 95% CI, 0.36-3.64; P = 0.81).ConclusionsThese findings suggest that pretransplantation hypoalbuminemia is associated with a higher risk for post-transplantation BKV and possibly CMV. More intense screening is warranted for these viruses in recipients with pretransplant hypoalbuminemia.

Project description:Background and objectivesManagement strategies are unclear for late-onset cytomegalovirus infection occurring beyond 6 months of antiviral prophylaxis in cytomegalovirus high-risk (cytomegalovirus IgG positive to cytomegalovirus IgG negative) kidney transplant recipients. Hybrid strategies (prophylaxis followed by screening) have been investigated but with inconclusive results. There are clinical and potential cost benefits of preventing cytomegalovirus-related hospitalizations and associated increased risks of patient and graft failure. We used decision analysis to evaluate the utility of postprophylaxis screening for late-onset cytomegalovirus infection.Design, setting, participants, & measurementsWe used the Markov decision analysis model incorporating costs and utilities for various cytomegalovirus clinical states (asymptomatic cytomegalovirus, mild cytomegalovirus infection, and cytomegalovirus infection necessitating hospitalization) to estimate cost-effectiveness of postprophylaxis cytomegalovirus screening strategies. Five strategies were compared: no screening and screening at 1-, 2-, 3-, or 4-week intervals. Progression to severe cytomegalovirus infection was modeled on cytomegalovirus replication kinetics. Incremental cost-effectiveness ratios were calculated as a ratio of cost difference between two strategies to difference in quality-adjusted life-years starting with the low-cost strategy. One-way and probabilistic sensitivity analyses were performed to test model's robustness.ResultsThere was an incremental gain in quality-adjusted life-years with increasing screening frequency. Incremental cost-effectiveness ratios were $783 per quality-adjusted life-year (every 4 weeks over no screening), $1861 per quality-adjusted life-year (every 3 weeks over every 4 weeks), $10,947 per quality-adjusted life-year (every 2 weeks over every 3 weeks), and $197,086 per quality-adjusted life-year (weekly over every 2 weeks). Findings were sensitive to screening cost, cost of hospitalization, postprophylaxis cytomegalovirus incidence, and graft loss after cytomegalovirus infection. No screening was favored when willingness to pay threshold was <$14,000 per quality-adjusted life-year, whereas screening weekly was favored when willingness to pay threshold was >$185,000 per quality-adjusted life-year. Screening every 2 weeks was the dominant strategy between willingness to pay range of $14,000-$185,000 per quality-adjusted life-year.ConclusionsIn cytomegalovirus high-risk kidney transplant recipients, compared with no screening, screening for postprophylactic cytomegalovirus viremia is associated with gains in quality-adjusted life-years and seems to be cost effective. A strategy of screening every 2 weeks was the most cost-effective strategy across a wide range of willingness to pay thresholds.

Dataset Information

Enhancement of Cytomegalovirus-Specific Cytokine Production after Modulation of the Costimulation in Kidney Transplant Patients.

Publications

Enhancement of Cytomegalovirus-Specific Cytokine Production after Modulation of the Costimulation in Kidney Transplant Patients.

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