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Grazyna Adamus, Lori Brown, Shayne Andrew, Gregory G. Burrows, Arthur A. Vandenbark; Antigen-Specific Immunotherapy Protects Optic Nerve from Inflammation and Demyelination in "Humanized" HLA-DR2 Mice with Optic Neuritis. Invest. Ophthalmol. Vis. Sci. 2011;52(14):2946.
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© ARVO (1962-2015); The Authors (2016-present)
Optic neuritis (ON) is a condition involving primary inflammation, demyelination, and axonal injury in the optic nerve, which contributes to the persistence of visual loss in patients with ON. The goal of this study was to evaluate an antigen-specific immunotherapy with a recombinant T-cell receptor ligand (RTL) drug for the treatment of ON in "humanized" HLA-DR2 (DRB1*1501) mice.
DR2 trangenic mice were immunized with myelin oligodendrocyte glycoprotein (MOG) 35-55 peptide in CFA containing 400 µg of M. tuberculosis s.c. Mice received 5 daily doses of 20 µg of RTL324m, comprised of MOG-35-55 linked linked to β1α1 MHC class II, at onset of ON.The optic nerve was evaluated at different time points for the presence of inflammatory cell infiltration on thin cross and longitudinal sections stained with H&E, axonal loss by Bielschowsky silver impregnation method, and myelin loss stained with luxol fast blue.
DR2 mice developed moderate to severe ON in addition to chronic EAE, which occurred 8 days after immunization. The lesions in the optic nerve correlated with the lesions in spinal cord and axonal injury was correlated with inflammation. Mice treated with vehicle showed a profound inflammation associated with confluent demyelination and axonal loss in both organs. Treatment with RTL324m significantly suppressed the development of clinical EAE (p<0.0005) and markedly reduced the incidence of pathologic ON (p<0.015). RTL342m suppressed inflammation, demyelination, and axonal loss. The anti-inflammatory effect of RTL treatment lasted for over 30 days whereas controls showed progressive neurodegeneration in the optic nerve and spinal cord.
RTL is a novel platform technology for anti-inflammatory treatment of many autoimmune-mediated diseases. Our findings show that RTL324m therapy targeting pathogenic T cells prevented inflammation associated with reduction of demyelination and axonal loss in ON. This study provides the foundation for the clinical application of RTL in patients with ON.
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