title: Age-Dependent Metabolic and Immunosuppressive Effects of Tacrolimus.
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.
authors.affiliation: Transplant Surgery Research Laboratory and Division of Transplant Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.|Department of Surgery, Campus Virchow-Klinikum and Campus Mitte, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: F
authors.initials: F
authors.lastname: Krenzien
authors.affiliation: Transplant Surgery Research Laboratory and Division of Transplant Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.|Department of General, Visceral and Transplant Surgery, Tübingen University Hospital, Tübingen, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Quante
authors.affiliation: Transplant Surgery Research Laboratory and Division of Transplant Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.|Department of Nephrology, Charité Campus Mitte, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: T
authors.initials: T
authors.lastname: Heinbokel
authors.affiliation: Transplant Surgery Research Laboratory and Division of Transplant Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.|Institute of Transplant Immunology, Hannover Medical School, Hannover, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Seyda
authors.affiliation: Transplant Surgery Research Laboratory and Division of Transplant Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.|Department of Urology, Osaka Medical College, Osaka, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Minami
authors.affiliation: Transplant Surgery Research Laboratory and Division of Transplant Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.|Department of Urology, Osaka Medical College, Osaka, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Uehara
authors.affiliation: Transplant Surgery Research Laboratory and Division of Transplant Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.|Division of Cardiovascular Surgery, University Hospital Zurich, Zurich, Switzerland.
authors.forename: H R C
authors.initials: HRC
authors.lastname: Biefer
authors.affiliation: Transplant Surgery Research Laboratory and Division of Transplant Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.
authors.forename: J M
authors.initials: JM
authors.lastname: Schuitenmaker
authors.affiliation: Renal and Pharmacy Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.
authors.forename: S
authors.initials: S
authors.lastname: Gabardi
authors.affiliation: Department of Surgery, Campus Virchow-Klinikum and Campus Mitte, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: K
authors.initials: K
authors.lastname: Splith
authors.affiliation: Department of Surgery, Campus Virchow-Klinikum and Campus Mitte, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: M
authors.initials: M
authors.lastname: Schmelzle
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.
authors.forename: A K
authors.initials: AK
authors.lastname: Petrides
authors.affiliation: Department of Urology, Osaka Medical College, Osaka, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Azuma
authors.affiliation: Department of Surgery, Campus Virchow-Klinikum and Campus Mitte, Charité-Universitätsmedizin Berlin, Berlin, Germany.
authors.forename: J
authors.initials: J
authors.lastname: Pratschke
authors.affiliation: Center for Immunobiology & Transplant Science, Houston Methodist Research Institute, Texas Medical Center, Houston, TX.
authors.forename: X C
authors.initials: XC
authors.lastname: Li
authors.affiliation: Transplant Surgery Research Laboratory and Division of Transplant Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.
authors.forename: A
authors.initials: A
authors.lastname: ElKhal
authors.affiliation: Transplant Surgery Research Laboratory and Division of Transplant Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.
authors.forename: S G
authors.initials: SG
authors.lastname: Tullius
mesh_terms: D000367:Age Factors; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D006084:Graft Rejection / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism*; D006085:Graft Survival / Q000187:drug effects*; D006801:Humans; D007166:Immunosuppressive Agents / Q000494:pharmacology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D016038:Skin Transplantation / Q000009:adverse effects*; D016559:Tacrolimus / Q000494:pharmacology*
chemical_list: D016207:Cytokines; D007166:Immunosuppressive Agents; D016559:Tacrolimus
keywords: basic (laboratory) research/science; calcineurin inhibitor (CNI); graft survival; immunobiology; immunosuppressant; immunosuppression/immune modulation; translational research/science