TY - JOUR
T1 - NK026680 inhibits T-cell function in an IL-2-dependent manner and prolongs cardiac allograft survival in rats
AU - Shibasaki, Susumu
AU - Yamashita, Kenichiro
AU - Goto, Ryoichi
AU - Oura, Tetsu
AU - Wakayama, Kenji
AU - Hirokata, Gentaro
AU - Shibata, Tomohiro
AU - Igarashi, Rumi
AU - Haga, Sanae
AU - Ozaki, Michitaka
AU - Todo, Satoru
N1 - Funding Information:
This study was supported in part by funding from the Nippon Kayaku Co., Ltd, Yutohkai, and Grant-in-Aid for Scientific Research from the Japan Society for the Promotion of Science, Japan.
PY - 2012/1
Y1 - 2012/1
N2 - 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.
AB - 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.
UR - https://www.scopus.com/pages/publications/82955188051
UR - https://www.scopus.com/pages/publications/82955188051#tab=citedBy
U2 - 10.1016/j.trim.2011.10.002
DO - 10.1016/j.trim.2011.10.002
M3 - Article
C2 - 22019622
AN - SCOPUS:82955188051
SN - 0966-3274
VL - 26
SP - 42
EP - 49
JO - Transplant Immunology
JF - Transplant Immunology
IS - 1
ER -