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Age‐Dependent Metabolic and Immunosuppressive Effects of Tacrolimus
Author(s) -
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.
Publication year - 2017
Publication title -
american journal of transplantation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.89
H-Index - 188
eISSN - 1600-6143
pISSN - 1600-6135
DOI - 10.1111/ajt.14087
Subject(s) - calcineurin , tacrolimus , immunosuppression , medicine , cytokine , clinical significance , immunology , t cell , cd8 , proinflammatory cytokine , pharmacology , transplantation , immune system , inflammation
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 CD 4 + T cells. In addition, TAC administration decreased interleukin ‐2 secretion in old CD 4 + T cells more effectively while inhibiting the proliferation of CD 4 + T cells in old mice. Both TAC ‐treated murine and human CD 4 + T cells demonstrated an age‐specific suppression of intracellular calcineurin levels and Ca 2+ influx, two critical pathways in T cell activation. Of note, depletion of CD 8 + T cells did not alter allograft survival outcome in old TAC ‐treated mice, suggesting that TAC age‐specific effects were mainly CD 4 + T cell mediated. Collectively, our study demonstrates age‐specific immunosuppressive capacities of TAC that are CD 4 + T cell mediated. The suppression of calcineurin levels and Ca 2+ influx in both old murine and human T cells emphasizes the clinical relevance of age‐specific effects when using TAC .