Inhibition of BTK and ITK with Ibrutinib Is Effective in the Prevention of Chronic Graft-versus-Host Disease in Mice.
Inhibition of BTK and ITK with Ibrutinib Is Effective in the Prevention of Chronic Graft-versus-Host Disease in Mice.
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DOI：
10.1371/journal.pone.0137641
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Yu XZ
中科院分区：
文献类型：
--
作者：
Schutt SD;Fu J;Nguyen H;Bastian D;Heinrichs J;Wu Y;Liu C;McDonald DG;Pidala J;Yu XZ
布鲁顿酪氨酸激酶（BTK）和IL-2诱导性T细胞激酶（ITK）分别是负责B细胞受体（BCR）信号传导和T细胞受体（TCR）信号传导途径中下游效应物的磷酸化和活化的酶。伊布替尼是FDA批准的BTK和ITK的强效抑制剂，可损害B细胞和T细胞功能。CD 4 T细胞和B细胞是诱导慢性移植物抗宿主病（cGVHD）所必需的。我们通过测试伊鲁替尼预防或改善cGVHD的能力来评估这些靶点，cGVHD是接受异基因造血干细胞移植（allo-HSCT）的患者的主要并发症之一。我们发现，在四种不同的小鼠模型中，伊布替尼显著减轻了cGVHD，并伴随着长期生存率的增加和临床评分的降低。与溶剂对照组相比，伊匹替尼治疗受者的临床改善与血清自身抗体、共刺激分子活化、B细胞增殖和肾小球肾炎降低相关。伊布替尼还能够减轻急性GVHD（aGVHD）的临床表现，其中接受者被给予具有或不具有B细胞的移植物，这表明伊布替尼对T细胞的抑制作用有助于aGVHD和cGVHD发病机制的降低。仍然缺乏有效的预防方案来降低allo-HSCT后人cGVHD的发生率和严重程度。我们的研究表明，伊曲替尼是一种有效的预防对几种小鼠模型的cGVHD的毒性最小，并可能是一个有前途的战略，以打击人类cGVHD临床。
Bruton’s Tyrosine Kinase (BTK) and IL-2 Inducible T-cell Kinase (ITK) are enzymes responsible for the phosphorylation and activation of downstream effectors in the B-cell receptor (BCR) signaling and T cell receptor (TCR) signaling pathways, respectively. Ibrutinib is an FDA-approved potent inhibitor of both BTK and ITK that impairs B-cell and T-cell function. CD4 T cells and B cells are essential for the induction of chronic graft-versus-host disease (cGVHD). We evaluated these targets by testing the ability of Ibrutinib to prevent or ameliorate cGVHD, which is one of the major complications for patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT). We found that Ibrutinib significantly alleviated cGVHD across four different mouse models, accompanied by increased long-term survival and reduced clinical score. The clinical improvements in Ibrutinib-treated recipients were associated with decreased serum-autoantibodies, costimulatory molecule activation, B-cell proliferation, and glomerulonephritis compared to vehicle controls. Ibrutinib was also able to alleviate the clinical manifestations in acute GVHD (aGVHD), where the recipients were given grafts with or without B cells, suggesting that an inhibitory effect of Ibrutinib on T cells contributes to a reduction in both aGVHD and cGVHD pathogenesis. An effective prophylactic regimen is still lacking to both reduce the incidence and severity of human cGVHD following allo-HSCT. Our study shows that Ibrutinib is an effective prophylaxis against several mouse models of cGVHD with minimal toxicity and could be a promising strategy to combat human cGVHD clinically.