Pharmacologic blockade of JAK1/JAK2 reduces GvHD and preserves the graft-versus-leukemia effect.
Pharmacologic blockade of JAK1/JAK2 reduces GvHD and preserves the graft-versus-leukemia effect.
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DOI：
10.1371/journal.pone.0109799
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
DiPersio JF
中科院分区：
文献类型：
--
作者：
Choi J;Cooper ML;Alahmari B;Ritchey J;Collins L;Holt M;DiPersio JF
我们最近报道，干扰素γ受体缺陷（IFNγR−/−）异基因供体T细胞导致的移植物抗宿主病（GvHD）显著低于野生型（WT）T细胞，同时在异基因造血干细胞移植（allo-HSCT）后保持抗白血病或移植物抗白血病（GvL）效应。我们证明了IFNγR信号通过在同种异体反应性T细胞中表达趋化因子受体CXCR 3来调节同种异体反应性T细胞向GvHD靶器官的运输。由于IFNγR信号传导通过JAK 1/JAK 2介导，我们测试了JAK 1/JAK 2抑制对GvHD的影响。虽然我们证明了使用JAK 1/JAK 2抑制剂INCB 018424在WT T细胞中药理学阻断JAK 1/JAK 2，（Ruxolitinib），在体外产生了与IFNγR−/− T细胞相似的作用，（T细胞中CXCR 3表达的减少）和体内尽管已经证实了INCB 018424的体内给药（allo-HSCT后GvHD的减轻），但仍有待确定INCB 018424的体内给药是否会导致GvL的保留同时减少GvHD。在这里，我们报告了INCB 018424在两种不同的小鼠MHC错配的allo-HSCT模型中以及使用两种不同的小鼠白血病模型（淋巴样白血病和髓样白血病）减少GvHD并保留有益的GvL效应。此外，INCB 018424的长期给药进一步提高了allo-HSCT后的生存率，并且优于其他JAK 1/JAK 2抑制剂（例如TG 101348或AZD 1480）的上级。这些数据表明，JAK 1/JAK 2的药理学抑制可能是一种有前途的治疗方法，以实现有益的抗白血病作用，并克服HLA屏障在allo-HSCT。除了GvHD之外，它还可以用于其他疾病，如器官移植排斥反应，慢性炎症性疾病和自身免疫性疾病。
We have recently reported that interferon gamma receptor deficient (IFNγR−/−) allogeneic donor T cells result in significantly less graft-versus-host disease (GvHD) than wild-type (WT) T cells, while maintaining an anti-leukemia or graft-versus-leukemia (GvL) effect after allogeneic hematopoietic stem cell transplantation (allo-HSCT). We demonstrated that IFNγR signaling regulates alloreactive T cell trafficking to GvHD target organs through expression of the chemokine receptor CXCR3 in alloreactive T cells. Since IFNγR signaling is mediated via JAK1/JAK2, we tested the effect of JAK1/JAK2 inhibition on GvHD. While we demonstrated that pharmacologic blockade of JAK1/JAK2 in WT T cells using the JAK1/JAK2 inhibitor, INCB018424 (Ruxolitinib), resulted in a similar effect to IFNγR−/− T cells both in vitro (reduction of CXCR3 expression in T cells) and in vivo (mitigation of GvHD after allo-HSCT), it remains to be determined if in vivo administration of INCB018424 will result in preservation of GvL while reducing GvHD. Here, we report that INCB018424 reduces GvHD and preserves the beneficial GvL effect in two different murine MHC-mismatched allo-HSCT models and using two different murine leukemia models (lymphoid leukemia and myeloid leukemia). In addition, prolonged administration of INCB018424 further improves survival after allo-HSCT and is superior to other JAK1/JAK2 inhibitors, such as TG101348 or AZD1480. These data suggest that pharmacologic inhibition of JAK1/JAK2 might be a promising therapeutic approach to achieve the beneficial anti-leukemia effect and overcome HLA-barriers in allo-HSCT. It might also be exploited in other diseases besides GvHD, such as organ transplant rejection, chronic inflammatory diseases and autoimmune diseases.
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