TY - JOUR
T1 - Dendritic cells conditioned with NK026680 prolong cardiac allograft survival in mice.
AU - Shibasaki, Susumu
AU - Yamashita, Kenichiro
AU - Yanagawa, Yoshiki
AU - Goto, Ryoichi
AU - Wakayama, Kenji
AU - Hirokata, Gentaro
AU - Tsunetoshi, Yusuke
AU - Zaitsu, Masaaki
AU - Igarashi, Rumi
AU - Haga, Sanae
AU - Ozaki, Michitaka
AU - Todo, Satoru
PY - 2012/6/27
Y1 - 2012/6/27
N2 - Pharmacologically modulated dendritic cells (DCs) can potentially regulate alloimmune responses. We examined the characteristics of immunoregulatory DCs induced by a novel triazolopyrimidine derivative, NK026680, which has been previously shown to inhibit DC maturation. DCs were generated from bone marrow progenitor cells from C57BL/6 (B6, H-2 haplotype) mice with granulocyte-macrophage colony-stimulating factor and interleukin (IL)-4. DCs were cultured with allogeneic BALB/c (H-2) splenocyte lysates with or without NK026680. DC functions were examined in vitro after stimulation of tumor necrosis factor α and in vivo by the intravenous injection of C3He/J (C3H, H-2) DCs cultured with B6 cell lysates and NK026680 into C3H mice. Seven days later, DC-treated mice received B6 heart allografts, and graft survival and alloimmune responses were assessed. In NK026680-treated DCs (NK-DCs), significant inhibition of the up-regulation of surface activation markers (CD40, CD80, CD86, and major histocompatibility complex class II) and IL-12 p40 production was observed after stimulation of tumor necrosis factor α compared with that of control DCs. Furthermore, NK-DCs suppressed alloreactive T-cell proliferation. The modulation of NK-DCs was likely associated with the inhibition of phosphorylation of p38 mitogen-activated protein kinase and the up-regulation of indolamine 2,3-dioxygenase expression. Compared with both noninjected and control DC-injected mice, mice that received a single in vivo infusion of NK-DCs showed significant increases in splenocyte IL-10 production and the splenic CD4 IL-10 T-cell population 7 days after injection, a significantly increased splenic CD4CD25FoxP3 T-cell population 14 days after injection, and markedly prolonged cardiac allograft survival. Ex vivo NK026680 conditioning allows DCs to acquire immunoregulatory properties that suppress alloimmune responses and prolong cardiac allograft survival.
AB - Pharmacologically modulated dendritic cells (DCs) can potentially regulate alloimmune responses. We examined the characteristics of immunoregulatory DCs induced by a novel triazolopyrimidine derivative, NK026680, which has been previously shown to inhibit DC maturation. DCs were generated from bone marrow progenitor cells from C57BL/6 (B6, H-2 haplotype) mice with granulocyte-macrophage colony-stimulating factor and interleukin (IL)-4. DCs were cultured with allogeneic BALB/c (H-2) splenocyte lysates with or without NK026680. DC functions were examined in vitro after stimulation of tumor necrosis factor α and in vivo by the intravenous injection of C3He/J (C3H, H-2) DCs cultured with B6 cell lysates and NK026680 into C3H mice. Seven days later, DC-treated mice received B6 heart allografts, and graft survival and alloimmune responses were assessed. In NK026680-treated DCs (NK-DCs), significant inhibition of the up-regulation of surface activation markers (CD40, CD80, CD86, and major histocompatibility complex class II) and IL-12 p40 production was observed after stimulation of tumor necrosis factor α compared with that of control DCs. Furthermore, NK-DCs suppressed alloreactive T-cell proliferation. The modulation of NK-DCs was likely associated with the inhibition of phosphorylation of p38 mitogen-activated protein kinase and the up-regulation of indolamine 2,3-dioxygenase expression. Compared with both noninjected and control DC-injected mice, mice that received a single in vivo infusion of NK-DCs showed significant increases in splenocyte IL-10 production and the splenic CD4 IL-10 T-cell population 7 days after injection, a significantly increased splenic CD4CD25FoxP3 T-cell population 14 days after injection, and markedly prolonged cardiac allograft survival. Ex vivo NK026680 conditioning allows DCs to acquire immunoregulatory properties that suppress alloimmune responses and prolong cardiac allograft survival.
UR - http://www.scopus.com/inward/record.url?scp=85027939243&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85027939243&partnerID=8YFLogxK
U2 - 10.1097/tp.0b013e3182516c9f
DO - 10.1097/tp.0b013e3182516c9f
M3 - Article
C2 - 22643332
AN - SCOPUS:85027939243
VL - 93
SP - 1229
EP - 1237
JO - Unknown Journal
JF - Unknown Journal
IS - 12
ER -