急性移植物抗宿主病(GVHD)是异基因造血干细胞移植(allo-HSCT)的主要并发症,具有显著的发病率和死亡率,和目前可用的治疗剂的功效是有限的。急性和慢性GVHD相似,两者都是由抗原呈递细胞和同种反应性B细胞和T细胞的激活引发的,随后导致炎症,组织损伤,器官衰竭。一个区别是急性GVHD主要归因于T细胞活化和细胞因子释放。而B细胞是慢性GVHD的关键参与者。伊布替尼是布鲁顿酪氨酸激酶(BTK)的不可逆抑制剂,这是B细胞受体信号的一部分。Ibrutinib目前用于治疗慢性GVHD,但其对急性GVHD的疗效尚不清楚。除了BTK,依鲁替尼还抑制白细胞介素2诱导型T细胞激酶(ITK),它主要在T细胞中表达,并且是激活TCR信号传导下游途径的关键酶。ITK激活PLCγ2并促进通过NF-κB的信号传导,NFAT,和MAPK,导致T细胞的活化和增殖并增强细胞因子的产生。因此,TCR信号通路对于急性GVHD的发生发展是不可缺少的,伊布替尼抑制ITK将是一种合理的治疗方法。
■一名56岁的男性急性髓系白血病患者,患有种系DEAD-boxRNA解旋酶41(DDX41)突变的髓系肿瘤,接受脐带血移植,并发展为严重的胃肠道(GI)急性GVHD,对类固醇和间充质干细胞治疗难以治疗。虽然急性GVHD持续存在多个危及生命的消化道出血事件,慢性皮肤GVHD发展,伊布鲁替尼420mg/日从移植第147天开始.尽管伊布替尼开始针对慢性GVHD,观察到急性GVHD的意外和突然缓解以及慢性GVHD的缓解。
■Ibrutinib是治疗急性GVHD的一种有前途的治疗剂,和进一步的研究是必要的。
UNASSIGNED: Acute graft-versus-host disease (GVHD) is a major complication of allogeneic hematopoietic stem cell transplantation (allo-HSCT) with significant morbidity and mortality, and efficacy of currently available therapeutics are limited. Acute and chronic GVHD are similar in that both are initiated by antigen presenting cells and activation of alloreactive B-cells and T-cells, subsequently leading to inflammation, tissue damage, and organ failure. One difference is that acute GVHD is mostly attributed to T-cell activation and cytokine release, whereas B-cells are the key players in chronic GVHD. Ibrutinib is an irreversible inhibitor of the Bruton\'s tyrosine kinase (BTK), which is part of B-cell receptor signaling. Ibrutinib is currently used for treating chronic GVHD, but its efficacy towards acute GVHD is unknown. Besides BTK, ibrutinib also inhibits interleukin-2 inducible T-cell kinase (ITK), which is predominantly expressed in T-cells and a crucial enzyme for activating the downstream pathway of TCR signaling. ITK activates PLCγ2 and facilitates signaling through NF-κB, NFAT, and MAPK, leading to activation and proliferation of T-cells and enhanced cytokine production. Therefore, the TCR signaling pathway is indispensable for development of acute GVHD, and ITK inhibition by ibrutinib would be a rational therapeutic approach.
UNASSIGNED: A 56-year-old male acute myeloid leukemia patient with Myeloid neoplasms with germline DEAD-box RNA helicase 41 (DDX41) mutation underwent cord blood transplantation and developed severe gastrointestinal (GI) acute GVHD which was refractory to steroids and mesenchymal stem cell therapy. While acute GVHD accommodated by multiple life-threatening GI bleeding events persisted, chronic cutaneous GVHD developed, and ibrutinib 420 mg/day was initiated from day 147 of transplant. Although ibrutinib was commenced targeting the chronic GVHD, unexpected and abrupt remission of acute GVHD along with remission of chronic GVHD was observed.
UNASSIGNED: Ibrutinib is a promising therapeutic for treating acute GVHD, and further studies are warranted.