Targeting MOG to skin macrophages prevents EAE in macaques through TGFβ-induced peripheral tolerance

Abstract

To study the effect of vaccination on tolerization to the myelin antigen MOG we used 26 a macaque model of experimental autoimmune encephalitis (EAE) in which immunization with 27 recombinant human myelin oligodendrocyte glycoprotein (rhMOG) elicits brain inflammation 28 and demyelination mediated by MOG-specific autoreactive CD4+ T lymphocytes and anti-MOG 29IgG. For antigen targeting to tolerizing antigen presenting cells, we used a recombinant antibody 30 directed to the Dendritic Cells (DC)-Asialoglycoprotein receptor (DC-ASGPR). The intradermal 31 administration of an anti-DC-ASGPR-MOG fusion protein, but not a control anti-DC-ASGPR-32 PSA (prostate specific antigen) protein, protected monkeys committed to develop EAE. 33Although effective treatment did not modify anti-MOG IgG production, it prevented the CD4+ T 34 lymphocyte activation and pro-inflammatory cytokine production. Moreover, animals treated 35 with anti-DC-ASGPR-MOG experienced a rise of MOG-specific CD4+CD25+FOXP3+CD39+ 36 regulatory T cells as well as a TGFb1, TGFb2 and IL-8 upsurge after rhMOG re-immunization. 37Our results indicate that the pathogenicity of autoantibodies directed to MOG is mitigated in the 38 presence of MOG-specific regulatory lymphocytes. This vaccination scheme appears suitable to 39 treat relapsing autoimmune diseases with identified autoantigens such as that harboring anti-40 MOG or anti-AQP4 autoantibodies. 41 42