Ursolic acid promotes robust tolerance to cardiac allografts in mice
Ursolic acid promotes robust tolerance to cardiac allografts in mice
复制标题
熊果酸促进小鼠对同种异体心脏移植物的强耐受性
DOI：
10.1111/j.1365-2249.2011.04333.x
复制
发表时间：
2011-05-01
影响因子：
4.6
通讯作者：
Zhou, P.
中科院分区：
文献类型：
--
作者：
Liu, Y.;Huang, X.;Zhou, P.
核因子（NF）-κ B B是T细胞活化的重要分子。我们以前的工作已经发现，T细胞限制性NF-κ B超阻遏物（I κ B alpha Delta N-Tg）小鼠，表达限制于T细胞区室的NF-κ B抑制剂，可以永久接受完全同种异体心脏移植物和二次供体皮肤移植物。在这项研究中，我们探讨了小分子抑制剂对NF-κ B的短暂抑制是否可以诱导移植物永久存活。熊果酸是一种小分子化合物，在体外剂量依赖性地抑制T细胞受体（TCR）触发的NF-κ B核转位和T细胞活化。在体内，熊果酸单药治疗显著延长小鼠心脏移植物的存活。在第0天辅助供体特异性输血（DST），熊果酸促进84.6%的首次心脏移植物存活超过150天。虽然具有长期存活移植物（LTS）的小鼠在没有任何治疗的情况下不排斥第二供体品系心脏超过100天，但它们都在14天内迅速排斥第三方品系心脏。有趣的是，该方案并未导致脾细胞中CD 4（+）CD 25（+）叉头盒P3（+）调节性T细胞比例增加。过继转移实验也不支持调控是该模型的主要机制。LTS的脾细胞对供体抗原的同种异体反应性降低。然而，CD 4（+）CD 25（+）调节性T细胞的耗竭并没有改变LTS脾细胞的供体反应性。这些数据表明，供体反应性T细胞的耗竭可能在该方案中发挥重要作用。
Nuclear factor (NF)-kappa B is an important molecule in T cell activation. Our previous work has found that T cell-restricted NF-kappa B super-repressor (I kappa B alpha Delta N-Tg) mice, expressing an inhibitor of NF-kappa B restricted to the T cell compartment, can permanently accept fully allogeneic cardiac grafts and secondary donor skin grafts. In this study, we explore if transient NF-kappa B inhibition by a small molecular inhibitor could induce permanent graft survival. Ursolic acid, a small molecular compound, dose-dependently inhibited T cell receptor (TCR)-triggered NF-kappa B nuclear translocation and T cell activation in vitro. In vivo, ursolic acid monotherapy prolonged significantly the survival of cardiac allograft in mice. Assisted with donor-specific transfusion (DST) on day 0, ursolic acid promoted 84.6% of first cardiac grafts to survive for more than 150 days. While the mice with long-term surviving grafts (LTS) did not reject the second donor strain hearts for more than 100 days without any treatment, they all promptly rejected the third-party strain hearts within 14 days. Interestingly, this protocol did not result in an increased proportion of CD4(+)CD25(+)forkhead box P3(+) regulatory T cells in splenocytes. That adoptive transfer experiments also did not support regulation was the main mechanism in this model. Splenocytes from LTS showed reduced alloreactivity to donor antigen. However, depletion of CD4(+)CD25(+) regulatory T cells did not alter the donor-reactivity of LTS splenocytes. These data suggest that depletion of donor-reactive T cells may play an important role in this protocol.