Age-Dependent Metabolic and Immunosuppressive Effects of Tacrolimus

F. Krenzien, M. Quante, T. Heinbokel, M. Seyda, K. Minami, H. Uehara, H. R.C. Biefer, J. M. Schuitenmaker, S. Gabardi, K. Splith, M. Schmelzle, A. K. Petrides, H. Azuma, J. Pratschke, X. C. Li, A. ElKhal, S. G. Tullius

Research output: Contribution to journalArticle

12 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)1242-1254
Number of pages13
JournalAmerican Journal of Transplantation
Volume17
Issue number5
DOIs
StatePublished - May 2017

Keywords

  • basic (laboratory) research/science
  • calcineurin inhibitor (CNI)
  • graft survival
  • immunobiology
  • immunosuppressant
  • immunosuppression/immune modulation
  • translational research/science

ASJC Scopus subject areas

  • Immunology and Allergy
  • Transplantation
  • Pharmacology (medical)

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