Mesenchymal stem cell exosomes exhibit anti-inflammatory effects on the ocular surface in a murine model of Stevens Johnson Syndrome and allergic eye disease

Abstract

Purpose : Immunotherapies are needed in inflammatory ocular surface diseases as an alternative to the blanket immunosuppression of steroids. Mesenchymal stem cell-derived exosomes (MSC-exo) have shown immunomodulatory and anti-fibrotic effects in corneal injury models. This study tested the therapeutic potential of MSC-exo for allergy-induced chronic ocular surface inflammation in Stevens Johnson Syndrome (SJS).

Methods : Transgenic mice expressing IKZF1-isoform, a transcription factor associated with SJS in humans, were used as a unique model of severe SJS-like inflammation. Mice were immunized with intraperitoneal (IP) ovalbumin in Alum and pertussis toxin and subsequently challenged with topical ovalbumin. MSC-exo were prepared from immortalized human embryonic stem cell-derived MSCs. Treatment groups (n=3) included: 1. naïve control; 2. BSS, 3. low dose (LD, 0.4μg) and 4. high dose (HD, 4μg) MSC-exo, and 5. loteprednol (0.5%) topically 4 times daily; 6. Subconjunctival (SC) MSC-exo (4μg) twice weekly; and 7. IP prednisolone (1mg/kg) daily. Clinical disease was evaluated daily for 7 days by tearing, conjunctival redness, eyelid edema, and chemosis (0-3). Immune cells and cytokines (IFNγ, IL-17, and IL-13) in the conjunctiva and cervical lymph nodes were analyzed by flow cytometry. Pharmacokinetics of topical and SC Alexa Fluor 488-labelled MSC-exo were tracked using in vivo multiphoton confocal microscopy.

Results : Topical MSC-exo treatment reduced total clinical scores (0-12) of induced allergic eye disease in a dose-dependent manner (p<0.001, LD and HD MSC-exo vs. BSS), with SC MSC-exo showing the most score reduction comparable to corticosteroids (p<0.001, SC MSC-exo vs. BSS). Populations of conjunctival CD4⁺ cells were reduced in the HD topical and SC MSC-exo groups. Expression of IFNγ, IL-13, and IL-17 were downregulated by MSC-exo, with SC MSC-exo showing the largest effect. Labelled MSC-exo were detectable for <3 hours after topical administration, while lasting in the SC space for at least 72 hours post-SC injection.

Conclusions : MSC-exo have therapeutic potential for targeted treatment of inflammatory ocular surface diseases such as SJS and may address a critical gap in treatment. Periocular administration of MSC-exo showed greater clinical effect and longer-lasting pharmacokinetics and opens possibilities as a novel therapy.

This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.