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T-cell exhaustion correlates with improved outcomes in kidney transplant recipients.

ABSTRACT: Continuous antigen stimulation during chronic infection or malignancy can promote functional T cell silencing, a phenomenon called T cell exhaustion. The prevalence and impact of T cell exhaustion following organ transplantation, another immune stimulus with persistently high antigen load, are unknown. Here, we characterized serially collected peripheral blood mononuclear cells from 26 kidney transplant recipients using time-of-flight mass cytometry (CyTOF) to define distinct subsets of circulating exhausted T cells and their relationship to induction therapy and allograft function. We observed an increase in specific subsets of CD4+ and CD8+ exhausted T cells from pre-transplant to 6-months post-transplant, with greater increases in participants given anti-thymocyte globulin induction than in participants who received no induction or non-depleting induction. The percentages of exhausted T cells at 6 months correlated inversely with adenosine triphosphate (ATP) production (a surrogate of T cell function) and with allograft interstitial fibrosis. Guided by the CyTOF data, we delineated a PD-1+CD57- phenotype for CD4+ and CD8+ exhausted T cells, and confirmed that these cells have limited capacity for cytokine secretion and ATP production. In an independent cohort of 50 kidney transplant recipients, we confirmed the predicted increase of PD-1+CD57- exhausted T cells after lymphocyte-depleting induction therapy and its direct correlation with better allograft function. Our findings suggest that monitoring T cell exhaustion can be useful for post-transplant risk assessment and support the need to develop and test strategies aimed at augmenting T cell exhaustion following kidney transplantation.

SUBMITTER: Fribourg M

PROVIDER: S-EPMC6650324 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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T-cell exhaustion correlates with improved outcomes in kidney transplant recipients.

Fribourg Miguel M Anderson Lisa L Fischman Clara C Cantarelli Chiara C Perin Laura L La Manna Gaetano G Rahman Adeeb A Burrell Bryna E BE Heeger Peter S PS Cravedi Paolo P

Kidney international 20190227 2

Continuous antigen stimulation during chronic infection or malignancy can promote functional T cell silencing, a phenomenon called T cell exhaustion. The prevalence and impact of T cell exhaustion following organ transplantation, another immune stimulus with persistently high antigen load, are unknown. Here, we characterized serially collected peripheral blood mononuclear cells from 26 kidney transplant recipients using time-of-flight mass cytometry (CyTOF) to define distinct subsets of circulat ...[more]

PMID: 31040060

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Project description:Background:Calcineurin inhibitors (CNI; cyclosporine, tacrolimus) are critical for kidney transplant immunosuppression, but have multiple potential drug interactions, such as with macrolide antibiotics. Macrolide antibiotics (clarithromycin, erythromycin, and azithromycin) are often used to treat atypical infections. Clarithromycin and erythromycin inhibit CNI metabolism and increase the risk of CNI nephrotoxicity, while azithromycin does not. Objective:To determine the frequency of CNI-macrolide co-prescriptions, the proportion who receive post-prescription monitoring, and the risk of adverse drug events in kidney transplant recipients. Design:Retrospective cohort study. Setting:We used linked health care databases in Alberta, Canada. Patients:We included 293 adult kidney transplant recipients from 2008-2015 who were co-prescribed a CNI and macrolide. Measurements:The primary outcome was a composite of all-cause hospitalization, acute kidney injury (creatinine increase ?0.3 mg/dL or 1.5 times baseline), or death within 30 days of the macrolide prescription. Methods:We identified CNI-macrolide co-prescriptions and compared outcomes in those who received clarithromycin/erythromycin versus azithromycin. We used a linear mixed-effects model to examine the mean change in serum creatinine and estimated glomerular filtration rate (eGFR). Results:Of the 293 recipients who were co-prescribed a CNI and a macrolide, 38% (n = 112) were prescribed clarithromycin/erythromycin while 62% (n = 181) were prescribed azithromycin. Compared with azithromycin users, clarithromycin/erythromycin users were less likely to have outpatient serum creatinine monitoring post-prescription (56% vs 69%, P = .03). There was no significant difference in the primary outcome between the 2 groups (17% vs 11%, P = .11); however, the risk of all-cause hospitalization was higher in the clarithromycin/erythromycin group (10% vs 3%, P = .02). The mean decrement in eGFR was significantly greater in the clarithromycin/erythromycin versus azithromycin group (-5.4 vs -1.9 mL/min/1.73 m2, P < .05). Limitations:We did not have CNI levels to correlate with the timing of CNI-macrolide co-prescriptions. We also did not have information regarding the indications for macrolide prescriptions. Conclusion:Clarithromycin and erythromycin were frequently co-prescribed in kidney transplant recipients on CNIs despite known drug interactions. Clarithromycin/erythromycin use was associated with a higher risk of hospitalization compared with azithromycin users. Safer prescribing practices in kidney transplant recipients are warranted.

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T-cell exhaustion correlates with improved outcomes in kidney transplant recipients.

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T-cell exhaustion correlates with improved outcomes in kidney transplant recipients.

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