Histone deacetylase inhibitor suberoylanilide hydroxamic acid reduces acute graft-versus-host disease and preserves graft-versus-leukemia effect
Histone deacetylase inhibitor suberoylanilide hydroxamic acid reduces acute graft-versus-host disease and preserves graft-versus-leukemia effect
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DOI：
10.1073/pnas.0400380101
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发表时间：
2004-03-16
影响因子：
11.1
通讯作者：
Ferrara, JLM
中科院分区：
文献类型：
--
作者：
Reddy, P;Maeda, Y;Ferrara, JLM
急性移植物抗宿主病(GVHD)和白血病复发是异基因骨髓移植(BMT)成功的两大障碍，异基因骨髓移植是治疗恶性血液病的有效方法。一些研究表明，促炎症细胞因子的失调和胃肠道完整性的丧失是GVHD的原因，而供者的细胞毒性反应是移植物抗白血病(GVL)保存的关键。琥珀酰苯胺异羟肟酸(SAHA)目前作为一种抗肿瘤药物正在进行临床试验，它抑制组蛋白脱乙酰酶的活性，并在低剂量下通过减少促炎细胞因子的产生而显示出抗炎作用。利用两种有代表性的小鼠骨髓移植模型，我们研究了SAHA对GVHD严重程度和GVL活性的影响。与赋形剂治疗动物相比，骨髓移植后+3天至+7天应用SAHA可降低血清促炎细胞因子水平，降低急性移植物抗宿主病的肠道组织病理学、临床严重度和死亡率。但在体内和体外，SAHA对供者T细胞的增殖和对宿主抗原的细胞毒反应均无影响。当小鼠在骨髓移植时接受致死剂量的肿瘤细胞时，通过使用两种不同的肿瘤和供体/受者组合，给予SAHA没有损害GVL活性，并显著提高了无白血病存活率。这些发现揭示了组蛋白脱乙酰酶抑制在导致GVHD的促炎事件中的关键作用，并提示这类药物可能提供一种策略来降低GVHD，同时保留细胞毒性T细胞对宿主抗原的反应，并维持有益的GVL效应。
Acute graft-versus-host disease (GVHD) and leukemic relapse are the two major obstacles to successful outcomes after allogeneic bone marrow transplantation (BMT), an effective therapy for hematological malignancies. Several studies have demonstrated that the dysregulation of proinflammatory cytokines and the loss of gastrointestinal tract integrity contribute to GVHD, whereas the donor cytotoxic responses are critical for graft-versus-leukemia (GVL) preservation. Suberoylanilide hydroxamic acid (SAHA) is currently in clinical trials as an antitumor agent, it inhibits the activity of histone deacetylases and at low doses exhibits anti inflammatory effects by reducing the production of proinflammatory cytokines. Using two well characterized mouse models of BMT, we have studied the effects of SAHA on GVHD severity and GVL activity. Administration of SAHA from day +3 to day +7 after BMT reduced serum levels of the proinflammatory cytokines and decreased intestinal histopathology, clinical severity, and mortality from acute GVHD compared with vehicle-treated animals. However, SAHA had no effect on donor T cell proliferative and cytotoxic responses to host antigens in vivo or in vitro. When mice received lethal doses of tumor cells at the time of BMT, administration of SAHA did not impair GVL activity and resulted in significantly improved leukemia-free survival by using two different tumor and donor/recipient combinations. These findings reveal a critical role for histone deacetylase inhibition in the proinflammatory events contributing to GVHD and suggest that this class of pharmacologic agents may provide a strategy to reduce GVHD while preserving cytotoxic T cell responses to host antigens and maintaining beneficial GVL effects.