Danielle S. LeServe, Marilla Garcia de Oliveira, Xiaoming Zhang, Taha Yahya, Toby Lanser, Christine Chen, Rafael M. Rezende and Howard L. Weiner
Rafael M. Rezende and Howard L. Weiner
Amyotrophic Lateral Sclerosis (ALS) is a neurodegenerative disease characterized by degeneration of motor neurons (MNs). Ninety percent of cases are sporadic (sALS), with no known genetic cause. The remaining ten percent of cases are familial (fALS), with a common genetic cause being the SOD1 mutation. Nasal administration of anti-CD3 monoclonal antibody (mAb) has been shown to induce IL-10 regulatory T cells (Tregs) in the cervical lymph nodes and their migration to the brain in the experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis. IL-10 secreted by these Tregs decreases neuroinflammation by switching the microglial neurodegenerative (MGnD) profile that contributes to inflammation to a homeostatic (M0), an anti-inflammatory profile. Here, we treated SOD1 G93A mice and wild-type littermate controls with nasal anti-CD3 or isotype control (IC) until the endpoint of the disease. We found that nasal administration of anti-CD3 mAb improved motor functions and delayed disease progression. Moreover, we found that nasal anti-CD3-induced changes in microglial gene signature at one month of treatment were associated with increased M0 decreased MGnD genes and increased genes related to phagocytosis and neurogenesis. Thus, these findings suggest that nasal anti-CD3 mAb administration may constitute a novel and promising immunotherapy for ALS.
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease associated with losing motor neurons. Environmental factors cause many cases of ALS, but inherited genes, including the SOD1 genetic mutation, cause ten percent of cases. We have previously shown that nasal treatment of anti-CD3 monoclonal antibody (mAb) induces IL-10-producing regulatory T cells (Tregs) in the cervical lymph nodes and their migration to the brain in a mouse model of multiple sclerosis. IL-10, an anti-inflammatory cytokine, decreases inflammation in the brain to change microglia profiles from a harmful neurodegenerative (MGnD) function to a healthy homeostatic (M0) and anti-inflammatory function. We treated SOD1 G93A and wild-type littermate mice with either anti-CD3 or isotype control (IC) until the endpoint of the disease. We found that treatment of anti-CD3 mAb improved motor abilities and extended life span. We also found that the nasal anti-CD3 mAb treatment changed the microglia profile, shifting from the harmful MGnD profile to the helpful M0 profile. These findings suggest that nasal anti-CD3 mAb treatment may be a promising treatment for ALS.