HDAC inhibitor reduces cytokine storm and facilitates induction of chimerism that reverses lupus in anti-CD3 conditioning regimen
HDAC inhibitor reduces cytokine storm and facilitates induction of chimerism that reverses lupus in anti-CD3 conditioning regimen
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DOI：
10.1073/pnas.0712051105
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发表时间：
2008-03-25
影响因子：
11.1
通讯作者：
Zeng, Defu
中科院分区：
文献类型：
--
作者：
Li, Nainong;Zhao, Dongchang;Zeng, Defu
在异基因造血细胞移植中，供者T细胞介导的移植物抗宿主白血病(GVL)和移植物抗自身免疫(GVA)活性在血液系统恶性肿瘤和难治性自身免疫性疾病的治疗中起着至关重要的作用。然而，移植物抗宿主病(GVHD)，有时可能是致命的，仍然是传统HCT的主要障碍，受者接受全身照射或大剂量化疗。我们以前报道过，抗CD3调节可以使供者CD8(+)T细胞促进植入，并在不引起GVHD的情况下介导GVL。然而，抗CD3抗体引发的细胞因子风暴综合征和诱导嵌合体所需的大剂量供体骨髓(BM)细胞阻碍了这种无辐射和GVHD预防预适应方案的临床应用。组蛋白脱乙酰酶(HDAC)抑制剂如琥珀酰苯胺异羟肟酸(SAHA)可诱导癌细胞凋亡，减少非恶性细胞产生致炎细胞因子。在这里，我们报告SAHA抑制抗CD3激活的T细胞的增殖和细胞毒活性。小剂量SAHA可减少细胞因子的产生，改善由抗CD3抗体引发的细胞因子风暴综合征。用抗CD3抗体和SAHA调节可以诱导老年非自身免疫性和自身免疫性狼疮小鼠与较低剂量供体BM细胞的嵌合体。此外，用抗CD3抗体和SAHA进行调节后，供者CD8(+)T细胞介导的GVA活性可以逆转狼疮性肾小球肾炎，而不会导致GVHD。这些结果表明，抗CD3和HDAC抑制剂的预适应是一种具有临床应用潜力的无辐射和预防GVHD的方案。
In allogeneic hematopoietic cell transplantation (HCT), donor T cell-mediated graft versus host leukemia (GVL) and graft versus autoimmune (GVA) activity play critical roles in treatment of hematological malignancies and refractory autoimmune diseases. However, graft versus host disease (GVHD), which sometimes can be fatal, remains a major obstacle in classical HCT, where recipients are conditioned with total body irradiation or high-dose chemotherapy. We previously reported that anti-CD3 conditioning allows donor CD8(+) T cells to facilitate engraftment and mediate GVL without causing GVHD. However, the clinical application of this radiation-free and GVHD preventative conditioning regimen is hindered by the cytokine storm syndrome triggered by anti-CD3 and the high-dose donor bone marrow (BM) cells required for induction of chimerism. Histone deacetylase (HDAC) inhibitors such as suberoylanilide hydroxamic acid (SAHA) are known to induce apoptosis of cancer cells and reduce production of proinflammatory cytokines by nonmalignant cells. Here, we report that SAHA inhibits the proliferative and cytotoxic activity of anti-CD3-activated T cells. Administration of low-dose SAHA reduces cytokine production and ameliorates the cytokine storm syndrome triggered by anti-CD3. Conditioning with anti-CD3 and SAHA allows induction of chimerism with lower doses of donor BM cells in old nonautoimmune and autoimmune lupus mice. In addition, conditioning with anti-CD3 and SAHA allows donor CD8(+) T cell-mediated GVA activity to reverse lupus glomerulonephritis without causing GVHD. These results indicate that conditioning with anti-CD3 and HDAC inhibitors represent a radiation-free and GVHD-preventative regimen with clinical application potential.