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Age-dependent metabolic and immunosuppressive effects of tacrolimus


Krenzien, F; Quante, M; Heinbokel, T; Seyda, M; Minami, K; Uehara, H; Biefer, H R C; Schuitenmaker, J M; Gabardi, S; Splith, K; Schmelzle, M; Petrides, A K; Azuma, H; Pratschke, J; Li, X C; ElKhal, A; Tullius, S G (2017). Age-dependent metabolic and immunosuppressive effects of tacrolimus. American Journal of Transplantation, 17(5):1242-1254.

Abstract

Immunosuppression in elderly recipients has been underappreciated in clinical trials. Here, we assessed age-specific effects of the calcineurin inhibitor tacrolimus (TAC) in a murine transplant model and assessed its clinical relevance on human T cells. Old recipient mice exhibited prolonged skin graft survival compared with young animals after TAC administration. More important, half of the TAC dose was sufficient in old mice to achieve comparable systemic trough levels. TAC administration was able to reduce proinflammatory interferon-γ cytokine production and promote interleukin-10 production in old CD4+ T cells. In addition, TAC administration decreased interleukin-2 secretion in old CD4+ T cells more effectively while inhibiting the proliferation of CD4+ T cells in old mice. Both TAC-treated murine and human CD4+ T cells demonstrated an age-specific suppression of intracellular calcineurin levels and Ca2+ influx, two critical pathways in T cell activation. Of note, depletion of CD8+ T cells did not alter allograft survival outcome in old TAC-treated mice, suggesting that TAC age-specific effects were mainly CD4+ T cell mediated. Collectively, our study demonstrates age-specific immunosuppressive capacities of TAC that are CD4+ T cell mediated. The suppression of calcineurin levels and Ca2+ influx in both old murine and human T cells emphasizes the clinical relevance of age-specific effects when using TAC.

Abstract

Immunosuppression in elderly recipients has been underappreciated in clinical trials. Here, we assessed age-specific effects of the calcineurin inhibitor tacrolimus (TAC) in a murine transplant model and assessed its clinical relevance on human T cells. Old recipient mice exhibited prolonged skin graft survival compared with young animals after TAC administration. More important, half of the TAC dose was sufficient in old mice to achieve comparable systemic trough levels. TAC administration was able to reduce proinflammatory interferon-γ cytokine production and promote interleukin-10 production in old CD4+ T cells. In addition, TAC administration decreased interleukin-2 secretion in old CD4+ T cells more effectively while inhibiting the proliferation of CD4+ T cells in old mice. Both TAC-treated murine and human CD4+ T cells demonstrated an age-specific suppression of intracellular calcineurin levels and Ca2+ influx, two critical pathways in T cell activation. Of note, depletion of CD8+ T cells did not alter allograft survival outcome in old TAC-treated mice, suggesting that TAC age-specific effects were mainly CD4+ T cell mediated. Collectively, our study demonstrates age-specific immunosuppressive capacities of TAC that are CD4+ T cell mediated. The suppression of calcineurin levels and Ca2+ influx in both old murine and human T cells emphasizes the clinical relevance of age-specific effects when using TAC.

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Additional indexing

Item Type:Journal Article, refereed, original work
Communities & Collections:04 Faculty of Medicine > University Hospital Zurich > Clinic for Cardiovascular Surgery
Dewey Decimal Classification:610 Medicine & health
Uncontrolled Keywords:basic (laboratory) research/science, , calcineurin inhibitor (CNI), , graft survival, immunobiology, , immunosuppressant, , immunosuppression/immune Modulation, , translational research/science
Language:English
Date:May 2017
Deposited On:01 Feb 2018 17:13
Last Modified:19 Feb 2018 10:50
Publisher:Wiley-Blackwell Publishing, Inc.
ISSN:1600-6135
OA Status:Closed
Free access at:Publisher DOI. An embargo period may apply.
Publisher DOI:https://doi.org/10.1111/ajt.14087
PubMed ID:27754593

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