NK026680 inhibits T-cell function in an IL-2-dependent manner and prolongs cardiac allograft survival in rats

Susumu Shibasaki, Kenichiro Yamashita, Ryoichi Goto, Tetsu Oura, Kenji Wakayama, Gentaro Hirokata, Tomohiro Shibata, Rumi Igarashi, Sanae Haga, Michitaka Ozaki, Satoru Todo

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

NK026680 is a triazolopyrimidine derivative that has been shown to inhibit dendritic cell maturation and activation. Here, we examined the immunosuppressive properties of NK026680 on T-cell function and assessed its immunosuppressive efficacy in an ACI (RT1 av1 haplotype) to Lewis (RT1 l) rat heart transplantation model. The effects of NK026680 on T-cell proliferation, activation, and cytokine production were investigated in vitro. Heart transplant recipient rats were administered NK026680 daily for 14days post-transplantation. In addition to graft survival time, alloimmune responses and graft histology at 4-10days post-transplantation were assessed. NK026680 was found to inhibit proliferation, CD25 upregulation, IL-2 production, and cell cycle progression in αCD3/αCD28-stimulated murine T cells. These effects were likely due to suppression of the p38 mitogen-activated protein kinase pathway and the subsequent inhibition of p65, c-Fos, and to a lesser extent, c-Jun. Daily NK026680 treatment suppressed alloimmune responses, prevented cellular infiltration into allografts, and prolonged graft survival. The anti-rejection effects of NK026680 were enhanced by tacrolimus. In conclusion, NK026680 inhibits the activation of T cells and prolongs cardiac allograft survival in rats. These features make it a potential candidate immunosuppressant for the treatment of organ transplant patients in the future.

Original languageEnglish
Pages (from-to)42-49
Number of pages8
JournalTransplant Immunology
Volume26
Issue number1
DOIs
Publication statusPublished - 01-2012

All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology
  • Transplantation

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