Abstract
Purpose :
Mucous membrane pemphigoid (MMP) is a chronic autoimmune systemic blistering disease, that severely affects the conjunctiva. Conjunctival involvement is critical since the autoantibody-induced inflammation results in progressive cornea and conjunctival scarring that may lead to visual impairment and blindness. Among the variety of expressed inflammatory cytokines, interleukin 8 (IL-8) is highly released and has been shown to play a role in clinical and experimental MMP. The purpose of the present study was to investigate the effects of topical ophthalmic administration of Ladarixin, an allosteric inhibitor of the IL-8 receptors CXCR1/2, in a mouse model of MMP.
Methods :
MMP disease was induced by repetitive subcutaneous (s.c.) injections of anti-mLAMα3 IgG (5mg/mouse) on alternating days (0, 2, 4, 6, 8 and 10) into 12 adult C57Bl/6 mice (males and females). Mice injected s.c. with IgG isolated from normal rabbit serum (NR IgG) served as negative control. Simultaneously with s.c. injections of anti-mLAMα3 IgG, mice were treated for 12 or 28 days twice a day with Ladarixin eye drops at 0.5% concentration or vehicle. Intraperitoneal injection of 20 mg/kg of methylprednisolone (MP) was used as positive reference standard (12 mice). Body weight, conjunctival lesions, inflammatory infiltration of conjunctiva, and levels of circulating total mouse IgG, were evaluated after 12 and 28 days of treatment. One-way-ANOVA with Dunnett's multiple comparisons test was used for statistical analyses.
Results :
Ladarixin eye drop treatment significantly decreased conjunctival lesions at both 12 (P=0.001) and 28 days (p=0.02) compared with vehicle control group. The reduced inflammation was macroscopically visible as shown by the lesion score of the affected eye area. The affected eye area was significantly reduced in the Ladarixin group (p=0.01) compared to the vehicle group at day 12. The leukocyte infiltration into the underlying subepithelial tissue was reduced after 28 days. Notably, Ladarixin eye drops were well tolerated and had no impact on body weight.
MP showed no effect on conjunctival lesions.
Conclusions :
Pharmacological inhibition of CXCR1/2 by topical Ladarixin reduces the clinical ocular manifestations in a mouse model of MMP. Topical ocular Ladarixin showed a promising therapeutic effect in these experimental conditions.
This abstract was presented at the 2023 ARVO Annual Meeting, held in New Orleans, LA, April 23-27, 2023.