MOG-induced Autoimmune Encephalomyelitis Research Articles

An engineered Fc fusion protein that targets antigen-specific T cells and autoantibodies mitigates autoimmune disease

Current effective therapies for autoimmune diseases rely on systemic immunomodulation that broadly affects all T and/or B cell responses. An ideal therapeutic approach would combine autoantigen-specific targeting of both T and B cell effector functions, including efficient removal of pathogenic autoantibodies. Albeit multiple strategies to induce T cell tolerance in an autoantigen-specific manner have been proposed, therapeutic removal of autoantibodies remains a significant challenge. Here, we devised an approach to target both autoantigen-specific T cells and autoantibodies by producing a central nervous system (CNS) autoantigen myelin oligodendrocyte glycoprotein (MOG)-Fc fusion protein. We demonstrate that MOG-Fc fusion protein has significantly higher bioavailability than monomeric MOG and is efficient in clearing anti-MOG autoantibodies from circulation. We also show that MOG-Fc promotes T cell tolerance and protects mice from MOG-induced autoimmune encephalomyelitis. This multipronged targeting approach may be therapeutically advantageous in the treatment of autoimmunity.

Maturation of circulating Ly6ChiCCR2+ monocytes by mannan-MOG induces antigen-specific tolerance and reverses autoimmune encephalomyelitis.

Autoimmune diseases affecting the CNS not only overcome immune privilege mechanisms that protect neural tissues but also peripheral immune tolerance mechanisms towards self. Together with antigen-specific T cells, myeloid cells are main effector cells in CNS autoimmune diseases such as multiple sclerosis, but the relative contributions of blood-derived monocytes and the tissue resident macrophages to pathology and repair is incompletely understood. Through the study of oxidized mannan-conjugated myelin oligodendrocyte glycoprotein 35-55 (OM-MOG), we show that peripheral maturation of Ly6ChiCCR2+ monocytes to Ly6ChiMHCII+PD-L1+ cells is sufficient to reverse spinal cord inflammation and demyelination in MOG-induced autoimmune encephalomyelitis. Soluble intradermal OM-MOG drains directly to the skin draining lymph node to be sequestered by subcapsular sinus macrophages, activates Ly6ChiCCR2+ monocytes to produce MHC class II and PD-L1, prevents immune cell trafficking to spinal cord, and reverses established lesions. We previously showed that protection by OM-peptides is antigen specific. Here, using a neutralizing anti-PD-L1 antibody in vivo and dendritic cell-specific Pdl1 knockout mice, we further demonstrate that PD-L1 in non-dendritic cells is essential for the therapeutic effects of OM-MOG. These results show that maturation of circulating Ly6ChiCCR2+ monocytes by OM-myelin peptides represents a novel mechanism of immune tolerance that reverses autoimmune encephalomyelitis.

Simultaneous Induction of CD4 T Cell Tolerance and CD8 T Cell Immunity by Semimature Dendritic Cells

Previous studies suggested that depending on their maturation state, dendritic cells (DC) could either induce T cell tolerance (immature and semimature DC) or T cell activation (mature DC). Pretreatment of C57BL/6 mice with encephalitogenic myelin oligodendrocyte glycoprotein (MOG)(35-55) peptide-loaded semimature DC protected from MOG-induced autoimmune encephalomyelitis. This protection was mediated by IL-10-producing CD4 T cells specific for the self Ag. Here we show that semimature DC loaded with the MHC class II-restricted nonself peptide Ag (OVA) induce an identical regulatory T cell cytokine pattern. However, semimature DC loaded simultaneously with MHC class II- and MHC class I-restricted peptides, could efficiently initiate CD8 T cell responses leading to autoimmune diabetes in a TCR-transgenic adoptive transfer model. Double-peptide-loaded semimature DC also induced simultaneously in the same animal partially activated CD8 T cells with cytolytic function as well as protection from MOG-induced autoimmune encephalomyelitis. Our study suggests that the decision between tolerance and immunity not only depends on the DC, but also on the type and activation requirements of the responding T cell.