We have previously demonstrated the unique properties of a new triazolopyrimidine derivative, NK026680, which exerts immunosuppressive effects in rat heart transplant model and confers tolerogeneic properties on ex vivo-conditioned dendritic cells in mice. We herein demonstrate that NK026680 promotes the expansion of regulatory T cells (Tregs) with potent immunoregulatory effects when used in combination with donor-specific transfusion (DST).

BALB/c (H-2^d) heart graft were transplanted into C57BL/6 (H-2^b) mice following intravenous injection of donor splenocytes (DST) and oral administration of NK026680. The NK026680 plus DST treatment markedly prolonged the survival time of the donor-graft, but not that of the 3rd party-graft (C3H; H-2^k). Treg cells in the recipient spleen on day 0 expanded when stimulated with donor-antigens in vivo and in vitro. After heart transplantation, Treg cells accumulated into the graft and increased in the spleen. NK026680 plus DST also decreased activated CD8⁺ T cells in the spleen and inhibited infiltration of CD8⁺ T cells into the graft. Depletion of CD25⁺ cells inhibited the graft prolonging effect of the NK026680 plus DST treatment.

NK026680 administration together with DST induces potent immunoregulatory effects in an antigen-specific manner, likely due to the in vivo generation of donor-specific Tregs.

我们之前已经证明了一种新的三唑并嘧啶衍生物 NK026680 的独特特性，它在大鼠心脏移植模型中发挥免疫抑制作用，并赋予小鼠体外条件树突状细胞耐受性。我们在此证明 NK026680 与供体特异性输血 (DST) 结合使用时，可促进具有有效免疫调节作用的调节性 T 细胞 (Tregs) 的扩增。

在静脉注射供体脾细胞 ( DST ) 和口服 NK026680 后，将BALB/c (H-2 ^d ) 心脏移植物移植到 C57BL/6 (H-2 ^{b ) 小鼠中。}NK026680 加DST治疗显着延长了供体移植物的存活时间，但不是第 3 方移植物 (C3H; H-2 ^k ) 的存活时间。在体内和体外用供体抗原刺激时，受体脾脏中的 Treg 细胞在第 0 天扩增。心脏移植后，Treg 细胞在移植物中积累并在脾脏中增加。NK026680 加DST还减少了脾脏中活化的 CD8 ⁺ T 细胞并抑制了 CD8 的浸润⁺ T 细胞进入移植物。CD25 ⁺细胞的消耗抑制了 NK026680 加DST处理的移植物延长作用。

NK026680 与DST一起给药以抗原特异性方式诱导有效的免疫调节作用，这可能是由于体内产生了供体特异性 Tregs。