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

Fovet, C.-M.; Stimmer, L.; Contreras, V.; Horellou, P.; Hubert, A.; Seddiki, N.; Chapon, C.; Tricot, S.; Leroy, C.; Flament, J.; Massonneau, J.; Tchitchek, N.; 't Hart, B.; Zurawski, S.; Klucar, P.; Deiva, K.; Zurawski, G.; Oh, S.; Le Grand, R.; Serguera, C.

doi:10.1101/571828

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bioRxiv · 10.1101/571828

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

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Abstract

To study the effect of vaccination on tolerization to the myelin antigen MOG we used a macaque model of experimental autoimmune encephalitis (EAE) in which immunization with recombinant human myelin oligodendrocyte glycoprotein (rhMOG) elicits brain inflammation and demyelination mediated by MOG-specific autoreactive CD4+ T lymphocytes and anti-MOG IgG. For antigen targeting to tolerizing antigen presenting cells, we used a recombinant antibody directed to the Dendritic Cells (DC)-Asialoglycoprotein receptor (DC-ASGPR). The intradermal administration of an anti-DC-ASGPR-MOG fusion protein, but not a control anti-DC-ASGPR-PSA (prostate specific antigen) protein, protected monkeys committed to develop EAE. Although effective treatment did not modify anti-MOG IgG production, it prevented the CD4+ T lymphocyte activation and pro-inflammatory cytokine production. Moreover, animals treated with anti-DC-ASGPR-MOG experienced a rise of MOG-specific CD4+CD25+FOXP3+CD39+ regulatory T cells as well as a TGF{beta}1, TGF{beta}2 and IL-8 upsurge after rhMOG re-immunization. Our results indicate that the pathogenicity of autoantibodies directed to MOG is mitigated in the presence of MOG-specific regulatory lymphocytes. This vaccination scheme appears suitable to treat relapsing autoimmune diseases with identified autoantigens such as that harboring anti-MOG or anti-AQP4 autoantibodies.

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Fovet, C.-M., Stimmer, L., Contreras, V., Horellou, P., Hubert, A., Seddiki, N., Chapon, C., Tricot, S., Leroy, C., Flament, J., Massonneau, J., Tchitchek, N., 't Hart, B., Zurawski, S., Klucar, P., Deiva, K., Zurawski, G., Oh, S., Le Grand, R., Serguera, C.. 2019-03-09. Targeting MOG to skin macrophages prevents EAE in macaques through TGFβ-induced peripheral tolerance. https://doi.org/10.1101/571828

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