Pathological progression of stroke in the peripheral and central nervous systems (PNS and CNS) is characterized by multiple converging signalling pathways that exacerbate neuroinflammation‐mediated secondary cell death. This creates a need for a novel type of immunotherapy capable of simultaneously lowering the synergistic inflammatory responses in the PNS and CNS, specifically the spleen and brain. Previously, we demonstrated that partial major histocompatibility complex (MHC) class II constructs can be administered subcutaneously to promote histological and behavioural effects that alleviate common symptoms found in a murine model of transient stroke. This MHC class II manipulates T cell cytokine expression in both PNS and CNS, resulting in dampened inflammation. In our long‐standing efforts towards translational research, we recently demonstrated that a potent next generation mouse‐based partial MHC class II construct named DRmQ (DRa1_L50Q‐mMOG‐35‐55) similarly induces neuroprotection in stroke rats, replicating the therapeutic effects of the human homolog as DRhQ (DRa1_L50Q‐human (h)MOG‐35‐55) in stroke mice. Our preclinical studies showed that DRmQ reduces motor deficits, infarct volume and peri‐infarct cell loss by targeting inflammation in this second species. Moreover, we provided mechanistic support in both animal studies that partial MHC class II constructs effectively modulate the spleen, an organ which plays a critical role in modulating secondary cell death. Together, these preclinical studies satisfy testing the constructs in two stroke models, which is a major criterion of the Stroke Therapy Academic Industry Roundtable (STAIR) criteria and a key step in effectively translating this drug to the clinic. Additional translational studies, including dose‐response and larger animal models may be warranted to bring MHC class II constructs closer to the clinic.

中文翻译：

---

脾脏参与部分 MHC II 类构建中风的神经保护作用。

外周和中枢神经系统（PNS 和 CNS）中风的病理进展的特点是多个会聚信号通路加剧了神经炎症介导的继发性细胞死亡。这就需要一种新型免疫疗法，能够同时降低 PNS 和 CNS，特别是脾脏和大脑中的协同炎症反应。以前，我们证明可以皮下施用部分主要组织相容性复合体 (MHC) II 类结构，以促进组织学和行为效应，从而减轻短暂性中风小鼠模型中的常见症状。这种 MHC II 类操纵 PNS 和 CNS 中的 T 细胞细胞因子表达，从而抑制炎症。在我们长期致力于转化研究的过程中，_L50Q ‐mMOG‐35‐55) 类似地诱导中风大鼠的神经保护作用，复制人类同系物 DRhQ (DRa1 _{L50Q)的治疗效果}-人 (h)MOG-35-55) 在中风小鼠中。我们的临床前研究表明，DRmQ 通过靶向第二个物种的炎症来减少运动缺陷、梗塞体积和梗塞周围细胞损失。此外，我们在两项动物研究中提供了机制支持，即部分 MHC II 类构建物有效调节脾脏，脾脏是调节继发性细胞死亡中起关键作用的器官。总之，这些临床前研究满足了在两种中风模型中测试结构，这是中风治疗学术行业圆桌会议 (STAIR) 标准的主要标准，也是将该药物有效转化为临床的关键步骤。可能需要进行额外的转化研究，包括剂量反应和更大的动物模型，以使 MHC II 类结构更接近临床。