Prevention of organ allograft rejection by a specific Janus kinase 3 inhibitor
Prevention of organ allograft rejection by a specific Janus kinase 3 inhibitor
复制标题
通过特定的 Janus 激酶 3 抑制剂预防器官同种异体移植排斥
DOI：
10.1007/s10353-004-0061-z
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发表时间：
2004
期刊：
影响因子：
--
通讯作者：
T. Wekerle
中科院分区：
文献类型：
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作者：
M. Säemann;F. Mühlbacher;G. Zlabinger;T. Wekerle
目前临床器官移植中的免疫抑制治疗是基于以非特异性方式抑制免疫系统的药物。这种全球免疫抑制与严重的副作用有关，包括感染和肿瘤。此外，这些药物还会影响免疫系统以外的细胞和器官。因此，这些药物有相当大的副作用，导致移植受者发病率增加和生活质量下降。临床免疫抑制的合理设计的重要一步将是识别/利用仅在免疫系统内发挥关键作用而不影响其他组织的分子靶点。从对严重联合免疫缺陷(SCID)患者的分析中发现，一种名为Janus kinase3(JAK3)的特定酪氨酸激酶在淋巴间隔室中起着重要作用。这种酪氨酸激酶的遗传缺失或消融与T细胞免疫缺陷有关，而其他器官系统没有明显的变化。JAK3看似非冗余和排他性的作用是什么？成熟的T细胞在多种细胞因子的作用下进入细胞周期，如IL-2、IL-4、IL-7、IL-9和IL-15。这些细胞因子结合在T淋巴细胞表面结构性表达的所谓的细胞因子公共伽马链(c-γ)上，而每个细胞因子都有自己独特的阿尔法链。由各自的α、β和始终相同的共同链组成的异三聚体复合体对激活T淋巴细胞至关重要。JAK3是一种必需的酪氨酸激酶，与共同的伽马链相关，它将每种细胞因子的激活信号传递到细胞内。JAK3激活的细胞因子途径的最终效应分子之一是STAT-5，因此被命名为JAK-STAT途径。除了JAK3在淋巴细胞中传递细胞因子信号的重要功能外，JAK3在T细胞激活的非常早期阶段的潜在功能以及在其他不同免疫细胞中的潜在功能是目前几项研究的主题，这些研究将JAK3作为潜在的免疫抑制靶标[1，2]。四年前，首次使用各种化学JAK3抑制剂的研究成功地证明，在同种异体器官或骨髓移植的啮齿动物模型中，同种异体移植物存活时间延长[3，4]。
Present immunosuppressive therapy in clinical organ transplantation is based on drugs that suppress the immune system in a non-specific way. This global immunosuppression is associated with severe side effects, including infections and tumors. Furthermore, these drugs affect cells and organ compartments other than the immune system. Hence these drugs have considerable side-effects leading to increased morbidity and reduced quality of life in transplant recipients. A major step forward in the rational design of clinical immunosuppression would be the identification/exploitation of molecular targets that play a critical role exclusively within the immune system without influencing other tissues. From the analysis of patients suffering from severe-combined immunodeficiency (SCID) it has been found that a specific tyrosine kinase called Janus kinase 3 (JAK3) has an essential role within the lymphoid compartment. Genetic absence or ablation of this tyrosine kinase is associated with defective T-cell immunity without apparent changes in other organ systems. What is the seemingly non-redundant and exclusive role of JAK3? Mature T-cells are driven into the cell cycle by several cytokines such as interleukin (IL) IL-2,-4,-7,-9 and IL-15. These cytokines bind to the so-called common-gamma chain of cytokines (cγ) that is constitutively expressed on the surface of T-lymphocytes, while each individual cytokine has its own specific alpha-chain. The heterotrimeric complex consisting of the respective alpha, beta and always the same commongamma chain is crucial for activating T lymphocytes. JAK3 is the essential tyrosine kinase associated with the common-gamma chain which transmits the activation signals by each cytokine into the cell. One of the final effector molecules of the activated cytokine pathway by JAK3 is STAT-5, hence the designation JAK-STAT pathway. Apart from the important function of JAK3 in transducing cytokine signals in lymphocytes, potential functions of JAK3 during the very early stages of T-cell activation and of JAK3 in other distinct immune cells are the topic of several present studies investigating this molecule as a potential immunosuppressive target [1, 2]. Four years ago the first studies employing various chemical JAK3 inhibitors successfully demonstrated a prolonged allograft survival in rodent models of allogeneic organ or bone marrow transplantation [3, 4].