Abstract
Objective: To investigate immune-modulatory mechanisms activated directly within the CNS by a novel innate-directed therapy for secondary progressive multiple sclerosis (SPMS).
Background: MIS416 is in a phase 2b placebo controlled efficacy trial for neurological improvement in SPMS patients. Formulated as a microparticle comprising NOD2 and TLR9 ligands, MIS416 enhances endogenous peripheral myeloid anti-inflammatory/tissue repair pathways which crosstalk with the CNS. Importantly, MIS416 may also exert a direct effect within the CNS as it traffics there homeostatically within a discrete subset of blood-derived monocytes. Direct effects of MIS416 within the CNS have not previously been described.
Design/Methods: To determine disease-suppressive effects of MIS416 within the CNS, we used intrathecal injection to cerebrospinal fluid to deliver MIS416 to the brains of mice.
Results: MIS416 induced IFNβ and IFNγ in the CNS of C57BL/6 mice. Mild infiltration of blood-derived myeloid cells was induced, and extraparenchymal leptomeningeal myeloid cells were among the cell sources of IFNβ and IFNγ. RNAseq and RT-qPCR showed induction of IFN-stimulated genes, including IRF7, CCL2, CXCL10, iNOS, and anti-inflammatory IL10.
Mice treated with MIS416 at EAE onset progressed less rapidly than control animals, indicative of disease-suppressive activity. This effect was reduced in mice lacking the Type I IFN receptor, arguing that intra-CNS NOD2- and TLR9-mediated Type I IFN induction may be one mechanism by which MIS416 acts to suppress MS-like disease.
Extraparenchymal myeloid cells phagocytosed fluorescent-tagged MIS416. Fluorescent myeloid cells were also detected in the parenchyma, identified as microglia. MIS416-containing microglia also produced Type I IFN. Mechanisms whereby MIS416 could access microglia to induce IFN include phagocytosis of apoptotic myeloid cells that migrated to parenchyma following phagocytosis of MIS416 in leptomeninges. This is supported by transfer of transgenic reporter cells.
Conclusions: MIS416 can directly activate innate anti-inflammatory programs by CNS-resident myeloid cells, leading to suppression of MS-like disease.
Study Supported by: The Danish Agency for Science, Technology and Innovation; The Danish Multiple Sclerosis Society.
Disclosure: Dr. Khorooshi has nothing to disclose. Dr. Wais has nothing to disclose. Dr. Webster has nothing to disclose. Dr. Owens has nothing to disclose.
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