TNF-alpha receptor fusion protein prevents experimental auto-immune encephalomyelitis and demyelination in Lewis rats: an overview.
To explore the therapeutic use of TNF-alpha inhibitors in human inflammatory demyelinating diseases we examined the effect of a recombinant TNFRp55 protein constructed by fusing TNFRp55 extracellular domain cDNA to a human IgG1 heavy gene fragment containing the hinge and constant domains CH2 and CH3 (TNFRp55-IgG1) in diverse experimental model systems representing inflammation and inflammatory demyelination of encephalitogenic T cells in vivo. In EAE actively induced by immunization of Lewis rats with MBP, a single dose of TNFRp55-IgG1 protected the recipient animals from clinical signs. Interestingly, the treatment neither prevented the formation CNS infiltrations, nor did it alter the cellular composition of the infiltrates. In EAE transferred by MBP specific activated T line cells, a model of inflammatory (not demyelinating) brain disease, the inhibitor's therapeutic effect on clinical disease was also striking achieving almost complete protection even after repeated transfers of encephalitogenic T cells. Finally, the recombinant inhibitor was also protective in Lewis rats with demyelinating experimental autoimmune panencephalitis produced by combined transfer of panencephalitogenic T cells and demyelinating monoclonal antibody specific for MOG. In this system, the T cells are of low encephalitogenic activity, but open the blood-brain barrier for the demyelinating immunoglobulins. 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 myelin specific autoimmunity raises hopes as to TNF-alpha directed therapy of human diseases like MS.
Klinkert
W E
WE
Department of Neuroimmunology, Max-Planck Institute for Psychiatry, Martinsried, Germany. klinkert@alf.biochem.mpg.de
Kojima
K
K
Lesslauer
W
W
Rinner
W
W
Lassmann
H
H
Wekerle
H
H
D000818:Animals; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000378:metabolism / Q000473:pathology* / Q000517:prevention & control*; D009186:Myelin Sheath / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology*; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D051381:Rats; D011917:Rats, Inbred Lew; D018124:Receptors, Tumor Necrosis Factor / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000627:therapeutic use*
D018696:Neuroprotective Agents; D018124:Receptors, Tumor Necrosis Factor; D011993:Recombinant Fusion Proteins