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Preliminary evaluation of safety and migration of immune activated mesenchymal stromal cells administered by subconjunctival injection for equine recurrent uveitis.
Abstract: Equine recurrent uveitis (ERU), an immune mediated disease characterized by repeated episodes of intra-ocular inflammation, affects 25% of horses in the USA and is the most common cause of glaucoma, cataracts, and blindness. Mesenchymal stromal cells (MSCs) have immunomodulatory properties, which are upregulated by preconditioning with toll-like receptor agonists. The objective was to evaluate safety and migration of TLR-3 agonist polyinosinic, polycytidylic acid (pIC)-activated MSCs injected subconjunctivally in healthy horses prior to clinical application in horses with ERU. We hypothesized that activated allogeneic MSCs injected subconjunctivally would not induce ocular or systemic inflammation and would remain in the conjunctiva for >14 days. Unassigned: Bulbar subconjunctiva of two horses was injected with 10 × 10 pIC-activated (10 μg/mL, 2 h) GFP-labeled MSCs from one donor three times at two-week intervals. Vehicle (saline) control was injected in the contralateral conjunctiva. Horses received physical and ophthalmic exams [slit lamp biomicroscopy, rebound tonometry, fundic examination, and semiquantitative preclinical ocular toxicology scoring (SPOTS)] every 1-3 days. Systemic inflammation was assessed via CBC, fibrinogen, and serum amyloid A (SAA). Horses were euthanized 14 days following final injection. Full necropsy and histopathology were performed to examine ocular tissues and 36 systemic organs for MSC presence via IVIS Spectrum. Anti-GFP immunohistochemistry was performed on ocular tissues. Unassigned: No change in physical examinations was noted. Bloodwork revealed fibrinogen 100-300 mg/dL (ref 100-400) and SAA 0-25 μg/mL (ref 0-20). Ocular effects of the subjconjucntival injection were similar between MSC and control eyes on SPOTS grading system, with conjunctival hypermia, chemosis and ocular discharge noted bilaterally, which improved without intervention within 14 days. All other ocular parameters were unaffected throughout the study. Necropsy and histopathology revealed no evidence of systemic inflammation. Ocular histopathology was similar between MSC and control eyes. Fluorescent imaging analysis did not locate MSCs. Immunohistochemistry did not identify intact MSCs in the conjunctiva, but GFP-labeled cellular components were present in conjunctival phagocytic cells. Unassigned: Allogeneic pIC-activated conjunctival MSC injections were well tolerated. GFP-labeled tracking identified MSC components phagocytosed by immune cells subconjunctivally. This preliminary safety and tracking information is critical towards advancing immune conditioned cellular therapies to clinical trials in horses.
Copyright © 2023 Cassano, Leonard, Martins, Vapniarsky, Morgan, Dow, Wotman and Pezzanite.
Publication Date: 2023-12-14 PubMed ID: 38162475PubMed Central: PMC10757620DOI: 10.3389/fvets.2023.1293199Google Scholar: Lookup The Equine Research Bank provides access to a large database of publicly available scientific literature. Inclusion in the Research Bank does not imply endorsement of study methods or findings by Mad Barn.
- Journal Article
Summary
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This research study investigates the safety and effectiveness of administering immune activated mesenchymal stromal cells (MSCs) via subconjunctival injection to potentially treat equine recurrent uveitis (ERU), a common horse disease affecting eyesight.
Background
- The primary focus of the research was equine recurrent uveitis (ERU), a disease that affects horses and causes repeated bouts of intra-ocular inflammation. This disease is a significant concern, given its prevalence, as it impacts approximately one in every four horses in the USA.
- The disease is the most frequent cause of certain eye conditions in horses, such as glaucoma, cataracts, and blindness.
- The research focused on the use of mesenchymal stromal cells (MSCs), which have immunomodulatory properties. Their application in treating ERU was considered, based on their upregulated properties when preconditioned with toll-like receptor (TLR) agonists.
Study Design
- The researchers injected TLR-3 agonist polyinosinic, polycytidylic acid (pIC)-activated MSCs subconjunctivally, or under the conjunctiva, in healthy horses to understand the potential reactions before being used with horses already affected by ERU.
- The study surmised that activated MSCs would not trigger inflammation either around the eyes or systemically, and they would remain in the conjunctiva for more than 14 days.
- The scientists injected pIC-activated MSCs, marked with a green fluorescent protein (GFP) label, into the conjunctiva of two healthy horses at intervals of two weeks, three times. The other eye was injected with a control saline solution for comparison.
- Regular physical and ophthalmic exams were conducted post-procedure every 1-3 days. Systemic inflammation was assessed via complete blood count (CBC), fibrinogen levels, and the presence of serum amyloid A (SAA).
- Post the final injection (after 14 days), the horses were euthanized and a full necropsy and histopathology examination were conducted to look for systemic inflammation and evidence of MSC presence.
Results
- The study didn’t observe any changes in the horses’ physical condition. The fibrinogen and SAA levels, significant indicators of systemic inflammation, remained within normal range.
- No significant differences were noted in the ophthalmic assessments of eyes injected with MSCs compared to the control eyes.
- Also, necropsy and histopathology revealed no signs of systemic inflammation or presence of MSCs.
- The conducted examinations showed that MSC parts were present within the phagocytic cells in the conjunctiva, indicating that the immune system had ingested these cells.
Conclusion
- This research concluded that the administration of pIC-activated MSCs via subconjunctival injection was well-tolerated by the horses in the study.
- The study provided critical preliminary data on the safety and tracking of MSCs, prerequisites for advancing to clinical trials in treating ERU in horses.
Cite This Article
APA
Cassano JM, Leonard BC, Martins BC, Vapniarsky N, Morgan JT, Dow SW, Wotman KL, Pezzanite LM.
(2023).
Preliminary evaluation of safety and migration of immune activated mesenchymal stromal cells administered by subconjunctival injection for equine recurrent uveitis.
Front Vet Sci, 10, 1293199.
https://doi.org/10.3389/fvets.2023.1293199 Publication
Researcher Affiliations
- Veterinary Institute for Regenerative Cures, School of Veterinary Medicine, University of California, Davis, Davis, CA, United States.
- Department of Medicine and Epidemiology, School of Veterinary Medicine, University of California, Davis, Davis, CA, United States.
- Department of Surgical and Radiological Sciences, School of Veterinary Medicine, University of California, Davis, Davis, CA, United States.
- Department of Ophthalmology & Vision Science, School of Medicine, University of California, Davis, Davis, CA, United States.
- Department of Surgical and Radiological Sciences, School of Veterinary Medicine, University of California, Davis, Davis, CA, United States.
- Veterinary Institute for Regenerative Cures, School of Veterinary Medicine, University of California, Davis, Davis, CA, United States.
- Department of Pathology, Microbiology, and Immunology, School of Veterinary Medicine, University of California, Davis, Davis, CA, United States.
- Department of Bioengineering, University of California, Riverside, Riverside, CA, United States.
- Department of Clinical Sciences, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO, United States.
- Department of Microbiology, Immunology and Pathology, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO, United States.
- Department of Clinical Sciences, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO, United States.
- Department of Clinical Sciences, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO, United States.
Conflict of Interest Statement
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
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