Antibody blockade of CD47‐SIRPα axis is protective in the murine model of Experimental Autoimmune Encephalomyelitis

Abstract

CD47 and its interaction with Signal Regulatory Protein alpha (SIRPα) play an important role in immune cell homeostasis. Our lab has previously demonstrated that CD47 on both endothelium and T cells plays an important role in T cell adhesion and diapedesis in vivo and in vitro, and that CD47−/− CD4+ T cells have impaired antigen‐mediated proliferation in the mouse model of Experimental Autoimmune Encephalomyelitis (EAE). Given the reports that CD47−/− mice and mice expressing a nonsignaling mutant SIRPα transgene are protected from developing EAE, suggests CD47 is a therapeutic target. However, a previous study found anti‐CD47 monoclonal antibody (mAb) MIAP301 treatment at the same time as myelin oligodendrocyte glycoprotein (MOG) immunization of mice delayed onset of disease and that treatment at peak of disease in animals resulted in a more severe disease. This “Janus like” effect has not been studied further. Using in vitro flow adhesion assays, here we show that mAb MIAP301 blocks both in cis (with LFA‐1 integrin) and in trans (with SIRPα) interactions of CD47 and that a different mAb MIAP410, blocks the SIRPα interaction and not LFA‐1‐ICAM‐1 interaction. We hypothesized that targeting only the “in trans” SIRPα interaction with MIAP410 in EAE would be protective. Thus we treated MOG immunized mice with MIAP410 or an isotype control IgG1 and investigated the leukocyte infiltration into the spinal cord using mass cytometry. Strikingly, treatment with MIAP410 prevented a more severe form of EAE when given at disease peak and was protective when given simultaneously with MOG. Mechanistically, MIAP410 had a profound inhibitory effect (68% inhibition) on the infiltration of IL‐23+ IFN‐γ producing γδ T cells into the spinal cord of the CNS with no significant differences observed on other immune cell infiltration such as Th17 cells. Additionally, we observed that there was decreased neutrophil and conventional dendritic cell infiltration in the spinal cord of MIAP410 as compared to IgG treated mice. Based on these findings, we conclude that CD47‐SIRPα interactions are necessary for the infiltration of pathogenic γδ T cells that express IL‐23R and promote leukocyte infiltration and neuronal damage in EAE.Support or Funding InformationT32 HL007627R01 HL125780RThis abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.