Intracerebral hemorrhage (ICH) is the most devastating type of stroke, with a disproportionately high mortality approaching 50% and a limited array of therapeutic options. ICH causes a primary injury followed by a secondary biochemical and cellular response, which involves the induction of the neuroinflammatory response, which has been shown to contribute to worsening neurological outcomes after ICH. The investigations in ICH have been hampered by the lack of effective and safe immunotherapeutic approaches that could target microglia (brain resident cells) inflammation and improve outcomes after ICH. Our laboratory found that nasal anti-CD3 treatment induces IL-10-secreting regulatory T cells (Tregs) that migrate to the brain and suppress microglia inflammation in a mouse model of multiple sclerosis. However, the potential of nasal anti-CD3 in modulating the immune response and enhancing the phagocytic and reparative capabilities of microglia post-ICH is still unexplored.

Nasal anti-CD3 increased CD4+ FoxP3+ Tregs and accelerated hematoma resolution by promoting microglia phagocytic capacity at 7 days post-ICH. It also modulated the microglia transcriptomic phenotype toward a reparative state with enhanced phagocytic machinery regulated by anti-inflammatory, neurotrophic, and growth factor signaling pathways such as IL-10, TGFB, and VEGF up to 1 month post-ICH. Finally, it reduced brain edema and improved functional motor and cognitive outcomes at 7 days and 1-month post-ICH.