Division of Molecular Medicine, Ruđer Bošković Institute, Zagreb, Croatia.
Department of Pharmacology, University of Oslo and Oslo University Hospital, Oslo, Norway.
Front Immunol. 2020 Oct 9;11:578314. doi: 10.3389/fimmu.2020.578314. eCollection 2020.
Chronic graft-versus-host disease (cGvHD) is a severe complication of allogeneic hematopoietic stem cell transplantation that affects various organs leading to a reduced quality of life. The condition often requires enduring immunosuppressive therapy, which can also lead to the development of severe side effects. Several approaches including small molecule inhibitors, antibodies, cytokines, and cellular therapies are now being developed for the treatment of cGvHD, and some of these therapies have been or are currently tested in clinical trials. In this review, we discuss these emerging therapies with particular emphasis on tyrosine kinase inhibitors (TKIs). TKIs are a class of compounds that inhibits tyrosine kinases, thereby preventing the dissemination of growth signals and activation of key cellular proteins that are involved in cell growth and division. Because they have been shown to inhibit key kinases in both B cells and T cells that are involved in the pathophysiology of cGvHD, TKIs present new promising therapeutic approaches. Ibrutinib, a Bruton tyrosine kinase (Btk) inhibitor, has recently been approved by the Food and Drug Administration (FDA) in the United States for the treatment of adult patients with cGvHD after failure of first-line of systemic therapy. Also, Janus Associated Kinases (JAK1 and JAK2) inhibitors, such as itacitinib (JAK1) and ruxolitinib (JAK1 and 2), are promising in the treatment of cGvHD. Herein, we present the current status and future directions of the use of these new drugs with particular spotlight on their targeting of specific intracellular signal transduction cascades important for cGvHD, in order to shed some light on their possible mode of actions.
慢性移植物抗宿主病（cGvHD）是异基因造血干细胞移植的一种严重并发症，可影响多种器官，导致生活质量下降。这种疾病通常需要长期的免疫抑制治疗，这也可能导致严重的副作用。目前正在开发几种方法来治疗 cGvHD，包括小分子抑制剂、抗体、细胞因子和细胞疗法，其中一些疗法已经或正在临床试验中进行测试。在这篇综述中，我们讨论了这些新兴的治疗方法，特别强调了酪氨酸激酶抑制剂（TKIs）。TKIs 是一类抑制酪氨酸激酶的化合物，从而阻止生长信号的传播和关键细胞蛋白的激活，这些蛋白参与细胞生长和分裂。因为它们已经被证明可以抑制 cGvHD 病理生理学中涉及的 B 细胞和 T 细胞中的关键激酶，所以 TKIs 提供了新的有前途的治疗方法。伊布替尼（ibrutinib），一种布鲁顿酪氨酸激酶（Btk）抑制剂，最近已被美国食品和药物管理局（FDA）批准用于治疗一线全身治疗失败的成人 cGvHD 患者。此外，Janus 相关激酶（JAK1 和 JAK2）抑制剂，如伊替替尼（JAK1）和鲁索替尼（JAK1 和 2），在治疗 cGvHD 方面也很有前途。本文介绍了这些新药的使用现状和未来方向，特别关注它们针对 cGvHD 重要的特定细胞内信号转导级联的靶向作用，以期阐明它们可能的作用机制。
