Development of a novel model of optic neuritis to assess neuroprotective and repair strategies in multiple sclerosis

Abstract

Multiple sclerosis (MS) is a putative autoimmune disease of the central nervous system (CNS), which often affects the optic nerve pathway. Optic neuritis (ON) is a clinical feature of MS that can cause loss of vision due to conduction block and demyelination. Visual function may not recover due to axonal loss in the optic nerve and subsequent loss of retinal ganglion cells (RGC) in the retina. The visual system is the most accessible and best studied part of the CNS and provides an ideal target to monitor the efficacy of strategies aimed at neuroprotection and repair. A C57BL/6 mouse expressing a T cell receptor (TCR) transgene specific for 35-55 residues of myelin oligodendrocyte glycoprotein (MOG), which develops ON spontaneously (approximately 5%) was characterised and an immunising protocol developed with a combination of immune adjuvants (Pertussis toxin, MOG-specific Z12 monoclonal antibody) to give a high incidence of disease. ON is associated with extensive axonal loss in the optic nerve and RGC loss in the retina. These animals were crossed with C57BL/6.Thy1 CFP mice, which express cyan fluorescent protein (CFP) under control of a Thy1 promoter that limits expression of CFP to the RGC in the eye. The resultant MOGTCRxThy1CFP mice develop ON leading to neuronal loss that can be monitored longitudinally in “real-time” in the living animal using techniques that correlate with studies undertaken in humans (visually evoked potentials, scanning laser ophthalmoscopy and optical coherence tomography). These techniques were used in the MOGTCRxThy1CFP to study neuroprotective and repair therapies for their potential in human trials. This novel model of optic neuritis will be invaluable for the study of neuroprotective and repair strategies in autoimmune diseases and offers a refinement of previous models of MS, such as “classical” EAE.