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Therapeutic Targeting of Retinal Immune Microenvironment With CSF-1 Receptor Antibody Promotes Visual Function Recovery After Ischemic Optic Neuropathy.

ABSTRACT: Retinal ischemia/reperfusion injury (RI) is a common cause of irreversible visual impairment and blindness in elderly and critical unmet medical need. While no effective treatment is available for RI, microglial activation and local immune responses in the retina are thought to play important roles in the pathophysiology of neurodegeneration. While survival and activation of microglia depend critically on colony-stimulating factor receptor (CSF-1R) signaling, it remains unclear if targeting the retinal immune microenvironments by CSF-1RAb after RI is sufficient to rescue vision and present a potentially effective therapy. Here we used rodent models of RI and showed that retinal ischemia induced by acute elevation of intraocular pressure triggered an early activation of microglia and macrophages in the retina within 12 h. This was followed by lymphocyte infiltration and increased production of pro-inflammatory cytokines. Intravitreal injection of CSF-1R neutralizing antibody (CSF-1RAb) after RI significantly blocked microglial activation and the subsequent T cell recruitment. This also led to improved retinal ganglion cell survival and function measured by cell quantification and electroretinogram positive scotopic threshold responses, as well as increased visual acuity and contrast sensitivity as assessed by optomotor reflex-based assays, when compared to the isotype-treated control group. Moreover, the administration of CSF-1RAb efficiently attenuated inflammatory responses and activation of human microglia in culture, suggesting a therapeutic target with human relevance. These results, together with the existing clinical safety profiles, support that CSF-1RAb may present a promising therapeutic avenue for RI, a currently untreatable condition, by targeting microglia and the immune microenvironment in the retina to facilitate neural survival and visual function recovery.

SUBMITTER: Tang Y

PROVIDER: S-EPMC7691249 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Therapeutic Targeting of Retinal Immune Microenvironment With CSF-1 Receptor Antibody Promotes Visual Function Recovery After Ischemic Optic Neuropathy.

Tang Yizhen Y Xiao Zebin Z Pan Li L Zhuang Dongli D Cho Kin-Sang KS Robert Kyle K Chen Xiaoxiao X Shu Lian L Tang Guangxian G Wu Jihong J Sun Xinghuai X Chen Dong F DF

Frontiers in immunology 20201113

Retinal ischemia/reperfusion injury (RI) is a common cause of irreversible visual impairment and blindness in elderly and critical unmet medical need. While no effective treatment is available for RI, microglial activation and local immune responses in the retina are thought to play important roles in the pathophysiology of neurodegeneration. While survival and activation of microglia depend critically on colony-stimulating factor receptor (CSF-1R) signaling, it remains unclear if targeting the ...[more]

PMID: 33281816

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Project description:PurposeOptical coherence tomography reveals retinal ganglion cell layer (GCL) and retinal nerve fiber layer (RNFL) thinning in chronic optic nerve injury. With acute optic nerve injury, as in acute nonarteritic anterior ischemic optic neuropathy (NAION), swelling obscures early demonstration of RNFL thinning, which might be used to evaluate therapies. We hypothesized that measurement of GCL plus inner plexiform layer (IPL) thickness and trajectory of thinning would show it is an earlier and more accurate biomarker of early permanent neuronal injury.MethodsWe prospectively studied 29 acute NAION eyes with standard automated perimetry and spectral domain (SD) optical coherence tomography for 6 months. We used a three-dimensional layer segmentation (method 1) and a commercial proprietary (method 2), to compute the combined thickness of macular GCL+IPL and method 2 to compute peripapillary RNFL thickness.ResultsAt presentation, the mean GCL+IPL thickness (78.7 μm ± 8.9) for NAION eyes, did not differ from unaffected fellow eyes (83 μm ± 6.4), using method 1 while method 2 (66.8 μm ± 18.7) failed in 34% of NAION eyes. At 1 to 2 months, 12% had RNFL loss compared to baseline, while 68% of NAION eyes had GCL+IPL thinning. The ganglion cell layer plus inner plexiform layer reduction was greatest at 1 to 2 months (19.6 μm ± 12.6) and was minimally worse after month 3. Ganglion cell layer plus inner plexiform layer thinning showed moderate to strong significant correlation with the visual acuity and mean deviation at each exam time. The retinal nerve fiber layer was not thinned until month 3.ConclusionsGanglion cell layer plus inner plexiform layer is acutely unaffected and provides a reliable measure of retinal neuronal structure using three-dimensional segmentation. Thinning develops within 1 to 2 months of onset, which is prior to RNFL swelling resolution. This suggests GCL+IPL measurement is better than the RNFL thickness to use as biomarker of early structural loss in NAION.

Project description:BackgroundThis study aimes to characterize the fundus structural changes in patients with nonarteritic anterior ischemic optic neuropathy (NAION) and the correlation between macular vessel density, retinal nerve fibre layer (RNFL) parameters and visual field sensitivity (VFS) in NAION patients.MethodsA retrospective case control study was performed using 37 eyes with NAION, 30 uninvolved contralateral eyes, and 27 eyes of healthy age-matched subjects. Data on the retinas and choroidal vessel densities and VFS were compared among the three groups.ResultsThe NAION group exhibited significantly lower RNFL thicknesses, lower ganglion cell complexes (GCC), larger global loss volume (GLV) values and focal loss volume (FLV) values when compared with both uninvolved eyes and healthy eyes (p?<?0.01 for all comparisons). The superficial vessel density (SVD) valus (whole, parafovea, superior-hemi and inferior-hemi) were significantly lower in NAION eyes, followed by uninvolved eyes and healthy eyes (p?<?0.01; LSD, p?<?0.05 for all comparisons). The deep vessel density (DVD) values (parafovea, superior-hemi and inferior-hemi) were the lowest by a significant value in NAION eyes, followed by uninvolved eyes and healthy eyes (p?<?0.01; LSD, p?<?0.05 for all comparisons). However, DVD value measurements (whole and fovea) of healthy and uninvolved eyes were not significantly different. The average threshold deviation (TD) was -?11.02?±?3.75?dB for the overall field region, -?6.01?±?2.21?dB for the affected superior field region and?-?9.98?±?3.34?dB for the affected inferior field region in NAION eyes. A statistically significant correlation was found between the RNFL thickness and visual field(VF) loss (r?=?-?0.788, p?<?0.001).ConclusionIn addition to peripapillary vascular changes occurring in NAION eyes, macular vessel density is also involved. Furthermore, NAION-uninvolved eyes exhibited abnormalities compared with healthy eyes. This indicates that vascular changes may occur before changes in retinal thickness at the early stages of NAION.

Dataset Information

Therapeutic Targeting of Retinal Immune Microenvironment With CSF-1 Receptor Antibody Promotes Visual Function Recovery After Ischemic Optic Neuropathy.

Publications

Therapeutic Targeting of Retinal Immune Microenvironment With CSF-1 Receptor Antibody Promotes Visual Function Recovery After Ischemic Optic Neuropathy.

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