NK026680 inhibits T-cell function in an IL-2-dependent manner and prolongs cardiac allograft survival in rats
| Autor: | Sanae Haga, Michitaka Ozaki, Gentaro Hirokata, Rumi Igarashi, Susumu Shibasaki, Kenichiro Yamashita, Tetsu Oura, Ryoichi Goto, Tomohiro Shibata, Kenji Wakayama, Satoru Todo |
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| Rok vydání: | 2011 |
| Předmět: |
Graft Rejection
Male CD3 Complex medicine.medical_treatment T cell T-Lymphocytes Immunology Pharmacology Lymphocyte Activation p38 Mitogen-Activated Protein Kinases Tacrolimus Mice Downregulation and upregulation CD28 Antigens Immunology and Allergy Medicine Animals Humans Transplantation Homologous IL-2 receptor Heart transplantation Transplantation Mice Inbred BALB C business.industry Graft Survival Dendritic cell Dendritic Cells Triazoles Rats Mice Inbred C57BL surgical procedures operative Cytokine medicine.anatomical_structure Pyrimidines Rats Inbred Lew Models Animal Heart Transplantation Interleukin-2 business Immunosuppressive Agents |
| Zdroj: | Transplant immunology. 26(1) |
| ISSN: | 1878-5492 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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