PURPOSE: Optic neuritis (ON) is a condition involving primary inflammation, demyelination, and axonal injury in the optic nerve and leads to apoptotic retinal ganglion cell (RGC) death, which contributes to the persistence of visual loss. Currently, ON has no effective treatment. The goal was to determine the effectiveness of immunotherapy with recombinant T-cell receptor ligand (RTL) in preventing ON in humanized HLA-DR2 transgenic mice. METHODS: Experimental autoimmune encephalomyelitis (EAE) was induced with myelin oligodendrocyte glycoprotein in humanized HLA-DR2 (DRβ1*1501) transgenic mice. Five consecutive doses of RTL342M were administrated at the onset of ON. The development of autoimmune ON was assessed by histopathology at different time points. The levels of myelin loss, axonal loss, and RGC damage were examined by immunofluorescence. RESULTS: HLA-DR2 mice developed chronic ON 2 days before EAE characterized by progressive neurodegeneration in both organs. RTL342M significantly suppressed inflammation in the optic nerve and spinal cord and provided protection for at least 30 days. Examination of myelin loss showed a marked suppression of demyelination and an increase in myelin recovery in the optic nerve. Moreover, RTL342M treatment revealed a neuroprotective effect on optic nerve axons and RGCs in retinas at postimmunization (PI) day 62. CONCLUSIONS: RTL342M suppressed clinical and histologic signs of EAE/ON by preventing the recruitment of inflammatory cells into the optic nerve and showed neuroprotective effects against ON. However, to achieve full therapeutic benefit, more doses may be needed. These findings suggest a possible clinical application of this novel class of T-cell-tolerizing drugs for patients with optic neuritis.
PURPOSE:Optic neuritis (ON) is a condition involving primary inflammation, demyelination, and axonal injury in the optic nerve and leads to apoptotic retinal ganglion cell (RGC) death, which contributes to the persistence of visual loss. Currently, ON has no effective treatment. The goal was to determine the effectiveness of immunotherapy with recombinant T-cell receptor ligand (RTL) in preventing ON in humanized HLA-DR2 transgenic mice. METHODS: Experimental autoimmune encephalomyelitis (EAE) was induced with myelin oligodendrocyte glycoprotein in humanized HLA-DR2 (DRβ1*1501) transgenic mice. Five consecutive doses of RTL342M were administrated at the onset of ON. The development of autoimmune ON was assessed by histopathology at different time points. The levels of myelin loss, axonal loss, and RGC damage were examined by immunofluorescence. RESULTS: HLA-DR2 mice developed chronic ON 2 days before EAE characterized by progressive neurodegeneration in both organs. RTL342M significantly suppressed inflammation in the optic nerve and spinal cord and provided protection for at least 30 days. Examination of myelin loss showed a marked suppression of demyelination and an increase in myelin recovery in the optic nerve. Moreover, RTL342M treatment revealed a neuroprotective effect on optic nerve axons and RGCs in retinas at postimmunization (PI) day 62. CONCLUSIONS: RTL342M suppressed clinical and histologic signs of EAE/ON by preventing the recruitment of inflammatory cells into the optic nerve and showed neuroprotective effects against ON. However, to achieve full therapeutic benefit, more doses may be needed. These findings suggest a possible clinical application of this novel class of T-cell-tolerizing drugs for patients with optic neuritis.
Authors: Roy W Beck; Jonathan D Trobe; Pamela S Moke; Robin L Gal; Dongyuan Xing; M Tariq Bhatti; Michael C Brodsky; Edward G Buckley; Georgia A Chrousos; James Corbett; Eric Eggenberger; James A Goodwin; Barrett Katz; David I Kaufman; John L Keltner; Mark J Kupersmith; Neil R Miller; Sarkis Nazarian; Silvia Orengo-Nania; Peter J Savino; William T Shults; Craig H Smith; Michael Wall Journal: Arch Ophthalmol Date: 2003-07
Authors: Cathleen Rich; Jason M Link; Alex Zamora; Helle Jacobsen; Roberto Meza-Romero; Halina Offner; Richard Jones; Gregory G Burrows; Lars Fugger; Arthur A Vandenbark Journal: Eur J Immunol Date: 2004-05 Impact factor: 5.532
Authors: Arthur A Vandenbark; Cathleen Rich; Jeff Mooney; Alex Zamora; Chunhe Wang; Jianya Huan; Lars Fugger; Halina Offner; Richard Jones; Gregory G Burrows Journal: J Immunol Date: 2003-07-01 Impact factor: 5.422
Authors: Marcos L Aranda; Diego Guerrieri; Gonzalo Piñero; María F González Fleitas; Florencia Altschuler; Hernán H Dieguez; María I Keller Sarmiento; Mónica S Chianelli; Pablo H Sande; Damián Dorfman; Ruth E Rosenstein Journal: Mol Neurobiol Date: 2019-05-01 Impact factor: 5.590
Authors: Roberta Brambilla; Galina Dvoriantchikova; David Barakat; Dmitry Ivanov; John R Bethea; Valery I Shestopalov Journal: J Neuroinflammation Date: 2012-09-10 Impact factor: 8.322
Authors: Lioba Horstmann; Heiko Schmid; André P Heinen; Florian C Kurschus; H Burkhard Dick; Stephanie C Joachim Journal: J Neuroinflammation Date: 2013-10-04 Impact factor: 8.322
Authors: Jie Pan; Julie Palmateer; Timothy Schallert; Madison Hart; Arushi Pandya; Arthur A Vandenbark; Halina Offner; Patricia D Hurn Journal: Transl Stroke Res Date: 2014-05-18 Impact factor: 6.829