Immune modulation by mannosylated peptides

Multiple Sclerosis is a degenerative disease of the central nervous system (CNS), involving autoimmunity against myelin, resulting in demyelination and paralysis. Antigen-specific immunotherapy may reduce this pathological autoimmunity, without disturbing normal immune function. This could be achieved by targeting of myelin antigens towards C-type lectin receptors (CLR) that recognize carbohydrate structures and are expressed on immune cells, because targeting of CLR under steady state conditions can suppress immunity in an antigen-specific way. In vitro studies showed that mannosylation of peptides results in internalization via the mannose receptor. In this study we observed, that immunization with mannosylated peptide does not induce disease in EAE, a model for Multiple Sclerosis. Instead, antigen-specific tolerance was induced; CNS inflammation was absent and DTH responses were impaired. Using transfer of TCR transgenic T cells in vivo we visualized that immunization with mannosylated peptide enhanced antigen presentation and induced vigorous expansion of T cells. However, T cells showed reduced blast formation and did not transfer EAE, despite normal production of inflammatory cytokines and chemokines. Lymphocytes accumulated in the lymph node of tolerized mice, which was counteracted by injection of Pertussis Toxin. Established EAE or ongoing DTH responses were ameliorated after mannosylated peptide treatment. In conclusion, mannosylated myelin peptide induced tolerance to EAE due to incomplete differentiation of encephalitogenic T cells and can be used to treat ongoing autoimmunity. Therefore, mannosylated antigens may represent a novel therapeutic approach for antigen-specific modulation of autoreactive T cells in vivo.Stichting Vrienden MS Research, TNO, Tebu Bio BVUBL - phd migration 201