Comparative Efficacy of Interleukin-7 and -15 Blockade in Alleviating Experimental Chronic Uveitis and Suppressing Pathogenic Memory CD4+ T Cells.

Abstract

Purpose: We have previously demonstrated the pathogenic function of memory CD4+ T cells, which express IL-7 receptor (IL-7R) and IL-15R, in experimental chronic autoimmune uveitis (CAU). Here, we aimed to compare the therapeutic efficacy of blocking IL-7 or IL-15 in CAU.

Methods: C57BL/6J mice were induced for CAU, then intraperitoneally injected with an anti-IL-7 antibody (Ab), an anti-IL-15 Ab, or an IgG control for 2 weeks. Disease was evaluated by weekly fundoscopy, optical coherence tomography (OCT), and full-field electroretinography for four weeks from the initiation of treatment. At week 4, retina and cervical lymph nodes (CLN) were collected for flow cytometry analysis of T-cell response.

Results: The anti-IL-7 Ab led to progressively reduced retinal infiltration and structural damage, with rapid recovery of retinal function. The anti-IL-15 Ab resulted in moderately reduced retinal infiltration and structural damage, along with a delayed, partial functional improvement. Compared to the control group, the anti-IL-7 Ab group exhibited significantly reduced disease scores from baseline on fundoscopy and OCT at week 4, and substantially improved dark-adapted (DA) a-wave and light-adapted b-wave responses at week 2; although the anti-IL-15 Ab group showed significantly improved disease from baseline only on OCT and increased DA b-waves at week 4. Both treatments effectively depleted the retinal infiltrating T cells and reduced memory Th17 cells in the CLN.

Conclusions: Our proof-of-concept study demonstrates that blocking IL-7 or IL-15 leads to specific depletion of the uveitogenic memory CD4+ T cells and disruption of disease chronicity in uveitis.