Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN, USA.
Department of Pediatric Medicine, Division of Critical Care Medicine, St. Jude Children's Research Hospital, Memphis, TN, USA.
Adv Exp Med Biol. 2024;1448:583-600. doi: 10.1007/978-3-031-59815-9_39.
Cytokine storm syndromes (CSSs) comprise a group of severe and often fatal hyperinflammatory conditions driven by the overproduction of pro-inflammatory cytokines by activated cells of the immune system. Many of the CSS-associated cytokines mediate their downstream effects by signaling through the Janus kinases (JAKs) and signal transducers and activators of transcription (STATs). In addition, several of these cytokines are produced downstream of JAK/STAT pathway activation. Therefore, targeting JAK/STAT signaling using small molecule JAK inhibitors has become an increasingly appealing therapeutic option to dampen hyperinflammation in patients with CSSs. Application of JAK inhibitors in preclinical CSS models has shown improvements in multiple sequelae of hyperinflammation, and there is growing clinical evidence supporting the efficacy of JAK inhibition in patients with these conditions. Although generally well tolerated, JAK inhibitor use is not without potential for toxicity, especially in settings like CSSs where end-organ dysfunction is common. More prospective clinical trials incorporating JAK inhibitors, alone or in combination with other immunomodulatory therapies, are necessary to determine the optimal dosing, schedule, efficacy, and tolerability of these agents for patients experiencing CSSs.
细胞因子风暴综合征（CSSs）是一组严重且常致命的过度炎症性疾病，由免疫系统激活细胞过度产生促炎细胞因子引起。许多与 CSS 相关的细胞因子通过信号转导子和转录激活子（STATs）与 Janus 激酶（JAKs）的信号转导来介导其下游效应。此外，这些细胞因子中的一些是在 JAK/STAT 通路激活的下游产生的。因此，使用小分子 JAK 抑制剂靶向 JAK/STAT 信号转导已成为一种越来越有吸引力的治疗选择，可以减轻 CSS 患者的过度炎症。在 CSS 临床前模型中应用 JAK 抑制剂已显示出对多种过度炎症后遗症的改善，并且越来越多的临床证据支持 JAK 抑制在这些情况下的疗效。尽管 JAK 抑制剂通常耐受性良好，但并非没有潜在毒性，尤其是在 CSS 等常见终末器官功能障碍的情况下。需要更多包含 JAK 抑制剂的前瞻性临床试验，单独或与其他免疫调节疗法联合使用，以确定这些药物在经历 CSS 的患者中的最佳剂量、方案、疗效和耐受性。
