Recombinant immune complexes (rICs) as a therapeutic for Multiple Sclerosis (MS): effect on myeloid cell activation

Abstract

Abstract Monocyte recruitment into the central nervous system (CNS) is critical for driving pathology in neuroinflammatory diseases such as MS. The monocytic influx as well as activation of resident myeloid cells contribute to recruitment and subsequent re-activation of autoreactive T cells, ultimately leading to demyelinating lesions, axonal damage, and progressive paralysis. Using the murine model for MS, experimental autoimmune encephalitis (EAE) we tested a rIC, M019, to determine its efficacy in reducing myeloid cell activation and subsequently reducing disease severity. Four days following induction of EAE with MOG peptide, daily treatment with M019 inhibited clinical symptoms including weight loss and demyelination in a dose-dependent manner. M019 also delayed or prevented disease in the SJL model of relapsing remitting EAE demonstrating its effectiveness against several forms of EAE. Analysis of the immune cell infiltrate in the spinal cords of M019 and vehicle treated mice revealed that M019 significantly inhibits the infiltration of myeloid and lymphoid cells into the CNS. The myeloid cells that were present in the CNS of M019 treated mice had reduced levels of MHC II suggesting they are inefficient at antigen presentation to autoreactive T cells. Microglia in the M019 treated EAE mice did not upregulate MHC II expression compared to the vehicle treated mice suggesting M019 inhibits their activation. M019 binds directly to monocytes in the periphery via CD16 (FcγRIII) and CD32 (FcγRII) and we detected increased chemokines in the sera of M019 treated EAE mice compared to vehicle treated EAE mice. These results suggest that M019 blocks immune cell migration into the CNS, potentially via phenotypic and functional changes to monocytes.