Modulating CNS neuroinflammation in animal models of intracerebral hemorrhage by nasal anti-CD3 (S4.010)

Abstract

<h3>Objective:</h3> Investigate the therapeutic benefit of nasal anti-CD3 treatment in animal model of ICH. <h3>Background:</h3> Intracerebral hemorrhage (ICH) is the most devastating type of stroke, with a disproportionately high mortality approaching 40%. Current investigations in ICH treatment have focused on limiting hematoma expansion which unfortunately, have not led to an effective treatment. Neuroinflammation play a critical role in secondary injury post-ICH. Exposure of brain parenchyma to blood products initiates a complex inflammatory cascade start with activation of resident microglia. Resulting cytokine release recruits circulating monocytes and lymphocytes, further enhancing inflammation, and contributing to secondary injury. The cellular and molecular mechanisms leading to neurological deficits following ICH are poorly understood, and there is no effective therapy to modulate the mitigate CNS injury and promote recovery. The mucosal immune system is a unique tolerogenic organ that provides a physiological approach for the induction of regulatory T cells (Tregs). We found that nasal anti-CD3 monoclonal antibody induces IL-10-secreting Tregs that migrate to the brain and suppresses microglial inflammation in a mouse model of multiple sclerosis. The therapeutic potential of the Tregs/IL-10 axis in ICH is largely unexplored. <h3>Design/Methods:</h3> We employed the collagenases model of ICH in mice and administered nasal anti-CD3 treatment within 24 hours of ICH which was continued up to 1-month post-bleed. We performed Flow cytometry, histopathology and behavioral analyses to characterize the cells and assess the effects of treatment on the behavioral outcomes at 1-month post-ICH. <h3>Results:</h3> Nasal anti-CD3 increased FoxP3+ Tregs and IL10 producing FoxP3+ Tregs in the brain. It also reduced microglial activation and lesion volume in the ipsilateral hemisphere post-ICH. Treatment improved behavioral outcomes, including motor, spatial learning, and hippocampal-dependent working memory functions at 1-month post-ICH. <h3>Conclusions:</h3> Our findings suggest that the nasal anti-CD3 may represent a novel therapeutic approach for treating ICH and potentially other types of acute brain injury. <b>Disclosure:</b> Dr. Izzy has received publishing royalties from a publication relating to health care. Taha Yahya has nothing to disclose. Dr. Cao has nothing to disclose. Dr. Waed has nothing to disclose. Dr. Moreira has nothing to disclose. Dr. Rezende has nothing to disclose. Dr. Weiner has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Genentech. Dr. Weiner has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Medday Pharmaceuticals. Dr. Weiner has received personal compensation in the range of $10,000-$49,999 for serving as a Consultant for vTv Therapeutics. Dr. Weiner has received personal compensation in the range of $5,000-$9,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Tiziana Life Sciences. Dr. Weiner has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for vTv Therapeutics. Dr. Weiner has received personal compensation in the range of $10,000-$49,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Medday Pharmaceuticals. Dr. Weiner has received personal compensation in the range of $10,000-$49,999 for serving as an officer or member of the Board of Directors for vTv Therapeutics. Dr. Weiner has received stock or an ownership interest from vTv Therapeutics. The institution of Dr. Weiner has received research support from National Institute of Health. The institution of Dr. Weiner has received research support from National MS Society. The institution of Dr. Weiner has received research support from Genzyme Corp. The institution of Dr. Weiner has received research support from Genentech, Inc. . The institution of Dr. Weiner has received research support from Verily Life Sciences LLC. The institution of Dr. Weiner has received research support from EMD Serono, Inc..