Preemptive HMG-CoA reductase inhibition provides graft-versus-host disease protection by Th-2 polarization while sparing graft-versus-leukemia activity
Preemptive HMG-CoA reductase inhibition provides graft-versus-host disease protection by Th-2 polarization while sparing graft-versus-leukemia activity
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DOI：
10.1182/blood-2007-08-106005
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发表时间：
2007-12-15
期刊：
影响因子：
20.3
通讯作者：
Negrin, Robert S.
中科院分区：
文献类型：
--
作者：
Zeiser, Robert;Youssef, Sawsan;Negrin, Robert S.
我们研究了阿托伐他汀(AT)是否能够跨越主要组织相容性复合体(MHC)错配障碍保护动物免受急性移植物抗宿主病(AGVHD)的侵袭。在供者的治疗中，过继转移的T细胞中诱导了Th-2细胞因子谱，并减少了它们在体内的扩张，这转化为显著降低了aGVHD的致死率。宿主治疗下调了受体抗原提呈细胞(APC)上的共刺激分子和MHC-II类分子的表达，增强了保护性他汀类药物的作用，而不影响移植物抗白血病(GVL)的活性。在STAT6(-/-)供体中，AT效应被部分逆转，并被甲氧丙戊酸L阻断，表明STAT6信号转导途径与L甲氧戊酸途径在AT介导的aGVHD保护中有关。在体内，GTP酶预烯基化水平降低，T-bet表达取消，c-MAF和GATA-3蛋白增加。因此，在维持GVL活性的同时，AT通过Th-2极化和抑制不受控制的Th-1反应对aGVHD的致死性具有显著的保护作用，鉴于AT的毒性适中，这一点具有重要的临床意义。
We investigated whether atorvastatin (AT) was capable of protecting animals from acute graft-versus-host disease (aGVHD) across major histocompatibility complex (MHC) mismatch barriers. AT treatment of the donor induced a Th-2 cytokine profile in the adoptively transferred T cells and reduced their in vivo expansion, which translated into significantly reduced aGVHD lethality. Host treatment down-regulated costimulatory molecules and MHC class II expression on recipient antigen-presenting cells (APCs) and enhanced the protective statin effect, without impacting graft-versus-leukemia (GVL) activity. The AT effect was partially reversed in STAT6(-/-) donors and abrogated by L-mevalonate, indicating the relevance of STAT6 signaling and the L-mevalonate pathway for AT-mediated aGVHD protection. AT reduced prenylation levels of GTPases, abolished T-bet expression, and increased c-MAF and GATA-3 protein in vivo. Thus, AT has significant protective impact on aGVHD lethality by Th-2 polarization and inhibition of an uncontrolled Th-1 response while maintaining GVL activity, which is of great clinical relevance given the modest toxicity profile of AT.