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  • Title: Dendritic cells conditioned with NK026680 prolong cardiac allograft survival in mice.
    Author: Shibasaki S, Yamashita K, Yanagawa Y, Goto R, Wakayama K, Hirokata G, Tsunetoshi Y, Zaitsu M, Igarashi R, Haga S, Ozaki M, Todo S.
    Journal: Transplantation; 2012 Jun 27; 93(12):1229-37. PubMed ID: 22643332.
    Abstract:
    BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: Ex vivo NK026680 conditioning allows DCs to acquire immunoregulatory properties that suppress alloimmune responses and prolong cardiac allograft survival.
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