title: The Impact of c-Fos/Activator Protein-1 Inhibition on Allogeneic Pancreatic Islet Transplantation.
abstract: Unpreventable allograft rejection is one of the main problems in pancreatic islet transplantation (PIT). Therefore, it is imperative to develop a more effective immunosuppressive strategy. The blockade of transcription factors has been a central part of T cell-depleting immunosuppressive therapies, as typified by the use of calcineurin inhibitors. The inhibition of activator protein-1 (AP-1) offers a novel strategy for immunosuppression in PIT, although to date, no reports on the effects of AP-1 inhibition are available. In this study, we investigated the immunosuppressive effects of T-5224, a c-Fos/AP-1-selective inhibitor, on murine T cells activated by αCD3+αCD28 mAbs. T-5224 inhibited proliferation, CD25 up-regulation, and the production of IL-2 and interferon-γ. In addition, T-5224 blocked the nuclear translocation of c-Fos/AP-1 in activated murine T cells. In BALB/c (H-2(d) )-to-C57BL/6J (H-2(b) ) mouse PIT, the 2-week administration of T-5224 prolonged survival of 600 islet allografts in a dose-dependent manner. When combined with a 2-week low-dose tacrolimus, the T-5224 treatment markedly prolonged allograft survival to over 300 days, while the efficacy was indeterminate when transplanted islet allograft mass was reduced to 300. We conclude that the c-Fos/AP-1 inhibition by T-5224 is a potentially attractive strategy for allogeneic PIT.
authors.affiliation: Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Yoshida
authors.affiliation: Department of Transplant Surgery, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
authors.forename: K
authors.initials: K
authors.lastname: Yamashita
authors.affiliation: Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Watanabe
authors.affiliation: Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Koshizuka
authors.affiliation: Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
authors.forename: D
authors.initials: D
authors.lastname: Kuraya
authors.affiliation: Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Ogura
authors.affiliation: Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Asahi
authors.affiliation: Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Ono
authors.affiliation: Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Emoto
authors.affiliation: Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Mizukami
authors.affiliation: Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Kobayashi
authors.affiliation: Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Shibasaki
authors.affiliation: Department of Pathology, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
authors.forename: U
authors.initials: U
authors.lastname: Tomaru
authors.affiliation: Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Kamachi
authors.affiliation: Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Matsushita
authors.affiliation: Department of Medicine, Kyushu University Beppu Hospital, Beppu, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Shiozawa
authors.affiliation: Laboratory of Physical Chemistry for Drug Design, School of Pharmacy, Kitasato University, Tokyo, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Hirono
authors.affiliation: Department of Gastroenterological Surgery I, Hokkaido University Graduate School of Medicine, Sapporo, Japan.
authors.forename: S
authors.initials: S
authors.lastname: Todo
mesh_terms: D000818:Animals; D001577:Benzophenones / Q000494:pharmacology / Q000627:therapeutic use*; D006084:Graft Rejection / Q000276:immunology / Q000517:prevention & control*; D007166:Immunosuppressive Agents / Q000494:pharmacology / Q000627:therapeutic use*; D016381:Islets of Langerhans Transplantation / Q000276:immunology*; D007555:Isoxazoles / Q000494:pharmacology / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016760:Proto-Oncogene Proteins c-fos / Q000037:antagonists & inhibitors; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D018808:Transcription Factor AP-1 / Q000037:antagonists & inhibitors; D014184:Transplantation, Homologous
chemical_list: C568912:3-(5-(4-(cyclopentyloxy)-2-hydroxybenzoyl)-2-((3-hydroxy-1,2-benzisoxazol-6-yl)methoxy)phenyl)propionic acid; D001577:Benzophenones; D007166:Immunosuppressive Agents; D007555:Isoxazoles; D016760:Proto-Oncogene Proteins c-fos; D018808:Transcription Factor AP-1
keywords: Basic (laboratory) research/science