Laquinimod treatment attenuates EAU by inhibiting both the inductive and effector phases in an APC-dependent manner
Listed in
This article is not in any list yet, why not save it to one of your lists.Abstract
Purpose
To evaluate the immunomodulatory effects on experimental autoimmune uveitis (EAU) of the aryl hydrocarbon receptor (AhR) agonist Laquinimod (LAQ), and its active metabolite DELAQ, with a focus on dendritic cell– and T cell–mediated mechanisms.
Methods
EAU was induced in mice by active immunization or by adoptive transfer of activated T cells. Mice were treated with LAQ either from the time of immunization or from 7 days after. Effects of LAQ were examined in wild-type, global AhR-knockout, or dendritic cell–conditional AhR knockout mice. Direct vs. indirect effects of AhR agonism on dendritic cells and T cells were studied in vitro using DELAQ, a major active metabolite of LAQ.
Results
LAQ treatment from Day 0 fully suppressed EAU, while delayed treatment (Day 7) provided only partial protection. In the adoptive transfer model, LAQ-treated recipients showed reduced pathology. Global AhR-deficient mice developed severe EAU comparable to that of wild-type mice, with an elevated Th17 response. LAQ-treated mice displayed increased frequencies of cDC1 and FoxP3⁺ regulatory T cells. In vitro, DELAQ activated AhR signaling and induced Ido1 and Ido2 expression in dendritic cells. DELAQ inhibited the activation of naïve and memory mouse T cells in an APC-dependent manner, as the response to anti-CD3/CD28 stimulation was unaffected. Importantly, DELAQ suppressed recall responses of human PBMC to tetanus toxoid.
Conclusions
LAQ protects against EAU by acting on AhR-expressing antigen-presenting cells to impair both priming and reactivation of pathogenic T cells. Its active metabolite DELAQ does not suppress T cells directly, but re-programs dendritic cells toward a tolerogenic, IDO-expressing phenotype that promotes immune regulation.
