Abstract: 161
Type: Scientific Session
Abstract Category: Pathology and pathogenesis of MS - Experimental models
Introduction: Retinal optical coherence tomography (OCT) is a clinical and research tool in MS. Both OCT and postmortem studies have shown significant retinal nerve fiber layer (RNFL) thinning and retinal ganglion cell (GC) loss in MS patients. However, the pathological underpinnings of OCT changes in MS have not been clearly defined. Retinal pathology has been described in certain experimental autoimmune encephalomyelitis (EAE) models, but dynamic OCT studies in EAE are scarce, and the best practices for the use of OCT in EAE have not been established.
Objective: To describe the dynamics of retinal injury after acute optic neuritis in different mouse models of EAE and define the optimal protocols for assessing neuroprotective therapies in EAE using OCT as an outcome measure.
Methods: Using spectral domain OCT (Heidelberg Spectralis), we monitored the thickness of the retinal layers with volume scans around the optic nerve head in different EAE models: in wild-type (WT) C57Bl/6 mice immunized with myelin oligodendrocyte glycoprotein (MOG35-55) or with intact myelin basic protein (MBP); in 2D2 mice immunized with MOG35-55; and in SJL mice immunized with myelin proteolipid lipoprotein (PLP139-151). We sham-immunized strain-matched mice as controls. At the end of each experiment, we counted GC density on retinal flat-mounts.
Results: Changes in retinal thickness over time were localized in the inner retinal layers (IRL: RNFL+ GC+ inner plexiform layer). In WT, MOG35-55 EAE eyes, progressive thinning of IRL started rapidly after the disease onset, with 1/3 of total loss happening during the initial 2 months (-4.25 ± 0.87 µm, P< 0.001 at month 2; -13.39 ± 1.33 µm, P< 0.001 at month 9). The severity of IRL thinning in the second month predicted GC loss (r2=0.59, P< 0.001) and the cumulative EAE score (r2=0.47, P< 0.001) by month 9. 2D2 mice immunized with MOG35-55 showed more severe EAE and retinal thinning. MBP immunization resulted in very mild disease course with no significant retinal changes. Because SJL mice are homozygous for the retinal degeneration 1 gene, sham-immunized SJL mice showed progressive IRL atrophy, which was accentuated in PLP-immunized mice.
Conclusions: IRL thinning develops quickly in certain EAE models. Changes in IRL thickness mirror neuronal loss and clinical severity in EAE. OCT studies screening neuroprotective therapies in MOG35-55 EAE should last two months and measure changes in the IRL as their primary readout.
Disclosure: Cruz-Herranz A: Research support from the National Multiple Sclerosis Society (Postdoctoral Fellowship), UCSF Program for Breakthrough Biomedical Research (Postdoctoral Independent Research Award), and the Conrad N. Hilton Foundation (Pilot Innovator Award).
Dietrich M: nothing to disclose
Hilla A: nothing to disclose
Yiu HH: nothing to disclose
Levin MH: nothing to disclose
Issberner A: nothing to disclose
Cordano C: Research support from the Fondazione Italiana Sclerosi Multipla (Research Fellowship).
Lehmann-Horn K: nothing to disclose
Balk LJ: nothing to disclose
Hartung HP: nothing to disclose
Aktas O: nothing to disclose
Zamvil SS: Research support from the National Institutes of Health (RO1 AI073737), National Multiple Sclerosis Society (RG 4768, RG 5179, and RG 1701), the Weill Institute and the Maisin Foundation.
Fischer D: nothing to disclose
Albrecht P: nothing to disclose
Green AJ: Research support from the National Multiple Sclerosis Society (Harry Weaver Neurosciences Scholar Award), Novartis, UCSF CTSI, That Man May See, and the Conrad N. Hilton Foundation (Pilot Innovator Award); personal fees from Inception Sciences and Mylan Pharmaceuticals; philanthropic support from the Rachleff Family and the Robert Dale Family. He also reports serving on an end point adjudication committee for Biogen and Medimmune. He serves on trial steering committees for Novartis and Scientific Advisory Board for Bionure
Abstract: 161
Type: Scientific Session
Abstract Category: Pathology and pathogenesis of MS - Experimental models
Introduction: Retinal optical coherence tomography (OCT) is a clinical and research tool in MS. Both OCT and postmortem studies have shown significant retinal nerve fiber layer (RNFL) thinning and retinal ganglion cell (GC) loss in MS patients. However, the pathological underpinnings of OCT changes in MS have not been clearly defined. Retinal pathology has been described in certain experimental autoimmune encephalomyelitis (EAE) models, but dynamic OCT studies in EAE are scarce, and the best practices for the use of OCT in EAE have not been established.
Objective: To describe the dynamics of retinal injury after acute optic neuritis in different mouse models of EAE and define the optimal protocols for assessing neuroprotective therapies in EAE using OCT as an outcome measure.
Methods: Using spectral domain OCT (Heidelberg Spectralis), we monitored the thickness of the retinal layers with volume scans around the optic nerve head in different EAE models: in wild-type (WT) C57Bl/6 mice immunized with myelin oligodendrocyte glycoprotein (MOG35-55) or with intact myelin basic protein (MBP); in 2D2 mice immunized with MOG35-55; and in SJL mice immunized with myelin proteolipid lipoprotein (PLP139-151). We sham-immunized strain-matched mice as controls. At the end of each experiment, we counted GC density on retinal flat-mounts.
Results: Changes in retinal thickness over time were localized in the inner retinal layers (IRL: RNFL+ GC+ inner plexiform layer). In WT, MOG35-55 EAE eyes, progressive thinning of IRL started rapidly after the disease onset, with 1/3 of total loss happening during the initial 2 months (-4.25 ± 0.87 µm, P< 0.001 at month 2; -13.39 ± 1.33 µm, P< 0.001 at month 9). The severity of IRL thinning in the second month predicted GC loss (r2=0.59, P< 0.001) and the cumulative EAE score (r2=0.47, P< 0.001) by month 9. 2D2 mice immunized with MOG35-55 showed more severe EAE and retinal thinning. MBP immunization resulted in very mild disease course with no significant retinal changes. Because SJL mice are homozygous for the retinal degeneration 1 gene, sham-immunized SJL mice showed progressive IRL atrophy, which was accentuated in PLP-immunized mice.
Conclusions: IRL thinning develops quickly in certain EAE models. Changes in IRL thickness mirror neuronal loss and clinical severity in EAE. OCT studies screening neuroprotective therapies in MOG35-55 EAE should last two months and measure changes in the IRL as their primary readout.
Disclosure: Cruz-Herranz A: Research support from the National Multiple Sclerosis Society (Postdoctoral Fellowship), UCSF Program for Breakthrough Biomedical Research (Postdoctoral Independent Research Award), and the Conrad N. Hilton Foundation (Pilot Innovator Award).
Dietrich M: nothing to disclose
Hilla A: nothing to disclose
Yiu HH: nothing to disclose
Levin MH: nothing to disclose
Issberner A: nothing to disclose
Cordano C: Research support from the Fondazione Italiana Sclerosi Multipla (Research Fellowship).
Lehmann-Horn K: nothing to disclose
Balk LJ: nothing to disclose
Hartung HP: nothing to disclose
Aktas O: nothing to disclose
Zamvil SS: Research support from the National Institutes of Health (RO1 AI073737), National Multiple Sclerosis Society (RG 4768, RG 5179, and RG 1701), the Weill Institute and the Maisin Foundation.
Fischer D: nothing to disclose
Albrecht P: nothing to disclose
Green AJ: Research support from the National Multiple Sclerosis Society (Harry Weaver Neurosciences Scholar Award), Novartis, UCSF CTSI, That Man May See, and the Conrad N. Hilton Foundation (Pilot Innovator Award); personal fees from Inception Sciences and Mylan Pharmaceuticals; philanthropic support from the Rachleff Family and the Robert Dale Family. He also reports serving on an end point adjudication committee for Biogen and Medimmune. He serves on trial steering committees for Novartis and Scientific Advisory Board for Bionure