Mannan-MOG35-55 Reverses Experimental Autoimmune Encephalomyelitis, Inducing a Peripheral Type 2 Myeloid Response, Reducing CNS Inflammation, and Preserving Axons in Spinal Cord Lesions.

Anastasia Dagkonaki,Lesley Probert,John Matsoukas,Theodore Tselios,Torben Ruhwedel,Vivian Tseveleki,Ioannis Kanistras,Lise Torp Jensen,Hans Lassmann,Maria Anagnostouli,Maria Evangelidou,Maria Avloniti,Fotis Lampros,Irini Papazian,Wiebke Möbius,Maria-Eleni Androutsou

doi:10.3389/fimmu.2020.575451

Abstract

CNS autoantigens conjugated to oxidized mannan (OM) induce antigen-specific T cell tolerance and protect mice against autoimmune encephalomyelitis (EAE). To investigate whether OM-peptides treat EAE initiated by human MHC class II molecules, we administered OM-conjugated murine myelin oligodendrocyte glycoprotein peptide 35-55 (OM-MOG) to humanized HLA-DR2b transgenic mice (DR2b.Ab°), which are susceptible to MOG-EAE. OM-MOG protected DR2b.Ab° mice against MOG-EAE by both prophylactic and therapeutic applications. OM-MOG reversed clinical symptoms, reduced spinal cord inflammation, demyelination, and neuronal damage in DR2b.Ab° mice, while preserving axons within lesions and inducing the expression of genes associated with myelin (Mbp) and neuron (Snap25) recovery in B6 mice. OM-MOG-induced tolerance was peptide-specific, not affecting PLP178-191-induced EAE or polyclonal T cell proliferation responses. OM-MOG-induced immune tolerance involved rapid induction of PD-L1- and IL-10-producing myeloid cells, increased expression of Chi3l3 (Ym1) in secondary lymphoid organs and characteristics of anergy in MOG-specific CD4+ T cells. The results show that OM-MOG treats MOG-EAE in a peptide-specific manner, across mouse/human MHC class II barriers, through induction of a peripheral type 2 myeloid cell response and T cell anergy, and suggest that OM-peptides might be useful for suppressing antigen-specific CD4+ T cell responses in the context of human autoimmune CNS demyelination.

Highlights

Autoimmune demyelinating disorders of the central nervous system (CNS) are a major cause of chronic neurologic disability in young adults
We established a reproducible EAE protocol in DR2b.Ab° mice by immunizing them with different amounts of MBP83-99, myelin oligodendrocyte glycoprotein (MOG), or hMOG, which differs from MOG by a single residue (S42 in MOG, P42 in hMOG), with or without an identical boost immunization 7 days later, each accompanied by pertussis toxin (PTx) injections
We previously showed that PLP139-151-induced EAE in SJL/J mice is prevented by prophylactic oxidized mannan (OM)-PLP139-151 but not OMMBP83-99, and that MOG-EAE in C57/BL6 mice (B6) mice is prevented by OMMOG but not OM-PLP178-191, demonstrating peptide specificity of OM-peptide tolerance [24]

Summary

Introduction

Autoimmune demyelinating disorders of the central nervous system (CNS) are a major cause of chronic neurologic disability in young adults. They include multiple sclerosis (MS), for which the autoimmune targets of CNS-infiltrating T and B lymphocytes are not yet fully understood [1], myelin oligodendrocyte glycoprotein (MOG) antibody associated disorders (MOGAD) which were previously considered to be part of the MS spectrum and in which the oligodendrocyte protein MOG is a major candidate autoantigen [2, 3], and neuromyelitis optica spectrum disorders (NMOSD) with an autoimmune response that targets aquaporin-4 on astrocytes. Therapeutic strategies that aim to re-establish peripheral tolerance selectively in myelin specific CD4+ T cells are a promising way forward for therapy in human autoimmune demyelination

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Results

Conclusion