Reinforcement of tolerance to myelin antigens, targeting CLR on Dendritic cells by glycan modified MOG
01 / 2007 - onbekend
The autoimmune disease sclerosis multiple (MS) induces neuronal demyelination caused among others by autoantibodies. A significant proportion of these antibodies are directed against the self myelin/oligodendrocyte glycoprotein (MOG). The suppression of anti-MOG autoimmunity should be an essential component of a therapy for MS. Common marmoset provides us a unique preclinical model due to its high similarity to human and the resemblance of marmoset model of experimental autoimmune encephalomyelitis (EAE) to MS. Immature dendritic cells (DC) control peripheral tolerance to self antigens through the balance between the signals provided by ligands of their C-type lectin receptors (CLR) and Toll-like receptors (TLR). The disturbed glycosylation of MOG can disrupt this homeostatic control deranging the union to CLR and promoting autoimmune reaction. The specific targeting of properly glycosylated myelin antigens such as MOG to CLR in immature DC will promote the induction of antigen-specific tolerance. T herefore, we started to investigate the glycosylation of native MOG from different sources to target CLR in DC. We will determine the configuration of the carbohydrate(s) epitope(s) by mass spectroscopy and HPLC analysing their binding to known CLR (DC-SIGN, MR, MGL). Once elucidated the glycan' epitopes on both normal and pathogenic MOG it is necessary to understand their contribution to a tolerant or autoimmunity state and their effect on in vitro assays of DC maturation and generation of regulatory or pathogenic T-cells. For the in vivo studies t he unglycosylated form of MOG (mMOG) will be used to induce EAE whereas the induction of tolerance during active EAE will be achieved by targeting normally glycosylated MOG (mMOGgly) to the CLR tolerogenic route in iDC. The restoration of the lack of response against critical components of CNS and a major goal in MS research will be achieved. These preclinical tests in non-human primates might predict the success of such a therapy in human.