Bioinformatics Research Trainee
Omar Albastaki, Taha Yahya, Tian Cao, MD, Michael Aronchik, Toby B Lanser, Danielle LeServe, Thais G Moreira, PhD, Wesley Nogueira Brandao, PhD, Joshua D. Bernstock, MD, PhD, Rajesh Krishnan, PhD, Rafael M. Rezende, PhD, Saef Izzy, MD, Howard L. Weiner, MD.
Howard L. Weiner, MD
Intracerebral hemorrhage (ICH) is the most devastating type of stroke, with a disproportionately high mortality approaching 50% and limited treatment 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 can target microglia and neuroinflammation. Here, we evaluated the role of nasal anti-CD3 monoclonal antibody, which is known to induce regulatory T cells, in a mouse collagenase model of ICH. We found that nasal anti-CD3 treatment increased CD4+ FoxP3+ Tregs and accelerated hematoma resolution by promoting microglia phagocytic capacity at 7 days following ICH. It also modulated the microglia phenotype toward a reparative transcriptomic 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 following ICH. Finally, treatment reduced brain edema, and improved functional motor and cognitive outcomes at 7 days and 1 month. Thus, nasal anti-CD3 represents a clinically applicable approach for ICH treatment.
Brain bleed is a life-threatening disease caused commonly by rupture of blood vessels in the brain. There are limited treatments options to control this disease. Brain bleed is associated with inflammation that involves the activation of immune cells and worsening neurological outcomes. Here, we tested a nasal spray treatment (anti-CD3) in a mouse model of brain bleed to modulate neuroinflammation (brain inflammation) and improve outcomes at 7 days and 1 month following bleed. We found that nasal anti-CD3 treatment accelerated bleeding resolution at 7 days after ICH. The treatment also changed microglia (brain resident cells) to a more healing and reparative state with anti-inflammatory properties up to 1 month after ICH. Treatment with nasal anti-CD3 also promoted recovery of movement and behavior in the mice at 1 month after bleeding. Based on our findings, nasal anti-CD3 therefore represents a promising approach for controlling brain inflammation and improving recovery after brain bleed.