TNF-ALPHA RECEPTOR FUSION PROTEIN PREVENTS EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS AND DEMYELINATION IN LEWIS RATS - AN OVERVIEW

To explore the therapeutic use of TNF-alpha inhibitors in human inflam matory demyelinating diseases we examined the effect of a recombinant TNFRp55 protein constructed by fusing TNFRp55 extracellular domain cDN A to a human IgG1 heavy gene fragment containing the hinge and constan t domains CH2 and CH3 (TNFRp55-IgG1) in diverse experimental model sys tems representing inflammation and inflammatory demyelination of encep halitogenic T cells in vivo. In EAE actively induced by immunization o f Lewis rats with MBP, a single dose of TNFRp55-IgG1 protected the rec ipient animals from clinical signs. Interestingly, the treatment neith er prevented the formation CNS infiltrations, nor did it alter the cel lar composition of the infiltrates. In EAE transferred by MBP specific activated T line cells, a model of inflammatory (not demyelinating) b rain disease, the inhibitor's therapeutic effect on clinical disease w as also striking achieving almost complete protection even after repea ted transfers of encephalitogenic T cells. Finally, the recombinant in hibitor was also protective in Lewis rats with demyelinating experimen tal autoimmune panencephalitis produced by combined transfer of panenc ephalitogenic T cells and demyelinating monoclonal antibody specific f or MOG. In this system, the T cells are of low encephalitogenic activi ty, but open the blood-brain barrier for the demyelinatin immunoglobul ins. The fusion protein treatment, however, prevented the formation of inflammatory lesions and demyelination. The strong therapeutic effect of the recombinant chimeric TNF-alpha inhibitor in three models of my elin specific autoimmunity raises hopes as to TNF-alpha directed thera py of human diseases like MS.