Abstract
Purpose :
Experimental autoimmune uveoretinitis (EAU) can be induced in rodents to study the organ-specific, T-cell mediated autoimmune response of the neural retina and related ocular tissues, including ciliary body, iris, and cornea. Rodent EAU pathology closely resembles human diseases in which patients display an immunological response to retinal antigens. A well-established rat model of EAU was used to evaluate the effects of topical ocular dosing with a small molecule inhibitor of Janu kinase (JAK). In this model, we hypothesized that the JAKi would mitigate the progression of EAU by effectively down-regulating disease-associated pro-inflammatory pathways, thereby signaling potential for therapeutic use.
Methods :
Lewis rats were immunized against IRBP (day 1) and EAU was allowed to develop over 16 days. Ophthalmic solutions of 0.03%, 0.1% and 0.3% Compound X and 0.1% Dexamethasone (Dex) phosphate (positive control) were applied topically TID, and a No Treatment group was included as a negative control. Masked dosing began on day 12 and the study terminated on day 16 which coincided with the severe portion of EAU progression. Between days 12 and 16 clinical signs of EAU were evaluated daily. Fundus images were gathered on day 16 and eyes were sent for histological sectioning, H&E staining, and analysis.
Results :
A significant reduction in clinical signs of autoimmune uveitis was observed for 0.1% Dex and Compound X. Fundus images showed that 0.1% Dex and Compound X reduced redness and observable signs of inflammation. Histological analysis demonstrated a marked reduction in immune infiltrate in the retina, ciliary body, iris, and anterior and posterior chambers. A dose-dependent decrease in autoimmune uveitis was observed for Compound X (0.03% < 0.1% < 0.3%) in all clinical and histological assessments; 0.3% and 0.1% were not significantly different from the positive control 0.1% Dex.
Conclusions :
In a rat EAU model, topical-ocular dosing with a novel JAKi significantly reduced inflammatory infiltrates and quelled clinical signs of uveitis. Specifically, our data indicate that 0.3% Compound X is as effective as 0.1% Dex at mitigating an organ-specific, T-cell mediated, autoimmune condition within the neural retina. These findings suggest that JAK inhibitors have potential as a novel class of compounds to treat inflammation-associated ocular diseases.
This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.