Chimeric antigen receptor T cell (CART) therapy, administration of certain T cell-agonistic antibodies, immune check point inhibitors, coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome–coronavirus 2 (SARS-CoV-2) and Toxic shock syndrome (TSS) caused by streptococcal as well as staphylococcal superantigens share one common complication, that is T cell-driven cytokine release syndrome (CRS) accompanied by multiple organ dysfunction (MOD). It is not understood whether the failure of a particular organ contributes more significantly to the severity of CRS. Also not known is whether a specific cytokine or signaling pathway plays a more pathogenic role in precipitating MOD compared to others. As a result, there is no specific treatment available to date for CRS, and it is managed only symptomatically to support the deteriorating organ functions and maintain the blood pressure. Therefore, we used the superantigen-induced CRS model in HLA-DR3 transgenic mice, that closely mimics human CRS, to delineate the immunopathogenesis of CRS as well as to validate a novel treatment for CRS. Using this model, we demonstrate that (i) CRS is characterized by a rapid rise in systemic levels of several Th1/Th2/Th17/Th22 type cytokines within a few hours, followed by a quick decline. (ii) Even though multiple organs are affected, small intestinal immunopathology is the major contributor to mortality in CRS. (iii) IFN-γ deficiency significantly protected from lethal CRS by attenuating small bowel pathology, whereas IL-17A deficiency significantly increased mortality by augmenting small bowel pathology. (iv) RNA sequencing of small intestinal tissues indicated that IFN-γ-STAT1-driven inflammatory pathways combined with enhanced expression of pro-apoptotic molecules as well as extracellular matrix degradation contributed to small bowel pathology in CRS. These pathways were further enhanced by IL-17A deficiency and significantly down-regulated in mice lacking IFN-γ. (v) Ruxolitinib, a selective JAK-1/2 inhibitor, attenuated SAg-induced T cell activation, cytokine production, and small bowel pathology, thereby completely protecting from lethal CRS in both WT and IL-17A deficient HLA-DR3 mice. Overall, IFN-γ-JAK-STAT-driven pathways contribute to lethal small intestinal immunopathology in T cell-driven CRS.

嵌合抗原受体 T 细胞 (CART) 疗法、某些 T 细胞激动性抗体的给药、免疫检查点抑制剂、严重急性呼吸系统综合症冠状病毒 2 (SARS-CoV-2) 和毒性引起的 2019 年冠状病毒病 (COVID-19)由链球菌和葡萄球菌超抗原引起的休克综合征 (TSS) 有一个常见的并发症，即 T 细胞驱动的细胞因子释放综合征 (CRS) 伴有多器官功能障碍 (MOD)。目前尚不清楚特定器官的衰竭是否对 CRS 的严重性影响更大。同样未知的是，与其他细胞因子或信号通路相比，特定的细胞因子或信号通路是否在诱发 MOD 方面发挥了更大的致病作用。因此，迄今为止没有针对 CRS 的特定治疗方法，并且仅对症处理以支持恶化的器官功能和维持血压。因此，我们在 HLA-DR3 转基因小鼠中使用了超级抗原诱导的 CRS 模型，该模型与人类 CRS 非常相似，以描绘 CRS 的免疫发病机制并验证 CRS 的新治疗方法。使用该模型，我们证明 (i) CRS 的特征是几种 Th1/Th2/Th17/Th22 型细胞因子的全身水平在几小时内迅速上升，然后迅速下降。(ii) 尽管多个器官受到影响，但小肠免疫病理学是 CRS 死亡率的主要原因。(iii) IFN-γ 缺乏通过减弱小肠病理显着保护免受致命性 CRS，而 IL-17A 缺乏通过增加小肠病理显着增加死亡率。(iv) 小肠组织的 RNA 测序表明 IFN-γ-STAT1 驱动的炎症通路结合促凋亡分子的增强表达以及细胞外基质降解导致 CRS 中的小肠病理。IL-17A 缺乏进一步增强了这些途径，并在缺乏 IFN-γ 的小鼠中显着下调。(v) Ruxolitinib 是一种选择性 JAK-1/2 抑制剂，可减弱 SAg 诱导的 T 细胞活化、细胞因子产生和小肠病理，从而在 WT 和 IL-17A 缺陷型 HLA-DR3 小鼠中完全防止致死性 CRS。总体而言，IFN-γ-JAK-STAT 驱动的途径有助于 T 细胞驱动的 CRS 中的致死性小肠免疫病理学。