NK026680 inhibits T-cell function in an IL-2-dependent manner and prolongs cardiac allograft survival in rats.
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 14 days post-transplantation. In addition to graft survival time, alloimmune responses and graft histology at 4-10 days 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.
Department of General Surgery, Graduate School of Medicine, Hokkaido University, Sapporo, Japan.
Susumu
S
Shibasaki
Kenichiro
K
Yamashita
Ryoichi
R
Goto
Tetsu
T
Oura
Kenji
K
Wakayama
Gentaro
G
Hirokata
Tomohiro
T
Shibata
Rumi
R
Igarashi
Sanae
S
Haga
Michitaka
M
Ozaki
Satoru
S
Todo
D000818:Animals; D018106:CD28 Antigens / Q000378:metabolism; D017252:CD3 Complex / Q000378:metabolism; D003713:Dendritic Cells / Q000187:drug effects; D006084:Graft Rejection / Q000188:drug therapy*; D006085:Graft Survival / Q000187:drug effects*; D016027:Heart Transplantation / Q000276:immunology*; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage*; D007376:Interleukin-2 / Q000032:analysis / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D011743:Pyrimidines / Q000008:administration & dosage*; D051381:Rats; D011917:Rats, Inbred Lew; D013601:T-Lymphocytes / Q000187:drug effects*; D016559:Tacrolimus / Q000008:administration & dosage; D014184:Transplantation, Homologous / Q000276:immunology; D014230:Triazoles / Q000008:administration & dosage*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
C509974:(S)-1-(5-hydroxy-1,5-dimethylhexyl)-3-(7-(4-methoxyphenyl)-(1,2,4-triazolo(1,5-a)pyrimidin-2-yl))urea; D018106:CD28 Antigens; D017252:CD3 Complex; D007166:Immunosuppressive Agents; D007376:Interleukin-2; D011743:Pyrimidines; D014230:Triazoles; D048051:p38 Mitogen-Activated Protein Kinases; D016559:Tacrolimus