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cerebral ischaemia, cytokines, immune response, major histocompatibility complex class II, middle cerebral artery occlusion, regenerative medicine, spleen

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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 (DRa1L50Q-mMOG-35-55) similarly induces neuroprotection in stroke rats, replicating the therapeutic effects of the human homolog as DRhQ (DRa1L50Q-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.

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CNS Neuroscience & Therapeautics, v. 26, issue 7, p. 663-669

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