The Impact of c-Fos/Activator Protein-1 Inhibition on Allogeneic Pancreatic Islet Transplantation.
Am J Transplant
; 15(10): 2565-75, 2015 Oct.
Article
em En
| MEDLINE
| ID: mdl-26012352
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.
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Base de dados:
MEDLINE
Assunto principal:
Benzofenonas
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Transplante das Ilhotas Pancreáticas
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Rejeição de Enxerto
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Imunossupressores
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Isoxazóis
Tipo de estudo:
Evaluation_studies
Limite:
Animals
Idioma:
En
Ano de publicação:
2015
Tipo de documento:
Article