Abstract
Purpose :
Visual impairment from optic neuritis (ON) is a common manifestation in aquaporin-4 (AQP4) autoantibody seropositive neuromyelitis optica spectrum disease (NMOSD). The purpose of our study was to determine whether human recombinant AQP4 antibodies (AQP4 rAb) with different antibody effector function elicits distinct patterns of optic nerve injury in an in vivo model of NMOSD ON.
Methods :
Long Evans rats (n=10/group) received a unilateral subarachnoid injection of 100 ng of anti-AQP4 recombinant antibody (AQP4 rAb) or isotype control (2B4) underneath the optic nerve sheath. AQP4 rAb contained either an intact human IgG1 Fc region (wt) or Fc region mutations that enhanced or diminish complement dependent (CDC) or antibody-dependent cellular (ADCC) cytotoxicity. Impairment in visual acuity and changes in retinal nerve fiber layer (RNFL) and retinal ganglion cell (RGC) complex thickness were determined 28 days later using optokinetic tracking response and optical coherence tomography. Statistical analyses were performed using ANOVA with Tukey’s test.
Results :
Injection of wt AQP4 rAb cause a decline in visual acuity when compared to rats having received isotype control 2B4 rAb (wt AQP4=0.34±0.03c/d vs. 2B4= 0.4±0.07c/d; p=0.02). Visual impairment was also observed in rats after injection of AQP4 rAb with enhanced CDC (CDC++/ADCC- AQP4=0.34±0.03c/d, p=0.001). When compared to baseline values recorded prior to injection, significant RNFL thinning was most evident in rats that have received either wt AQP4 or AQP4 rAb with enhanced CDC and ADCC (percentage RNFL loss in wt AQP4=-10±3%, p=0.002; CDC+++/ADCC+ AQP4=-9±5%, p=0.023). Mutated AQP4 rAb without ADCC function (CDC++/ADCC-) showed intermediate loss (-6±3%, p=0.32). No RNFL thickness loss was noticed in animals having received 2B4 (-1±5%) or mutated AQP4 rAb with ablated CDC (CDC-/ADCC++= 0±3%). Analysis of the RGC complex revealed significant thinning in rats injected with wt AQP4 (77±3 µm, p=0.003), CDC++/ADCC- AQP4 (76±4 µm, p=0.003), and CDC+++/ADCC+ AQP4 (76±4 µm, p=0.003) when compared to rats having received either 2B4 rAb (87±3 µm) or CDC-/ADCC++ AQP4 rAb (82±3 µm).
Conclusions :
Similar to models of intracerebral NMOSD pathology, NMOSD optic nerve injury is dependent on targeting the AQP4 water channel through antibody-mediated CDC. Magnitude of visual impairment and RGC degeneration were differentially impacted by ADCC.
This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.