Characterization and Validation of In Vitro and In Vivo Models to Investigate TNF-α-Induced Inflammation in Retinal Diseases

Overall, our study describes valuable in vitro and in vivo approaches to study the function of TNF-α in retinal inflammation and demonstrated a preclinical proof-of-mechanism treatment with golimumab. Translational relevance: The AAV-based model expressing human TNF-α allows us to investigate TNF-α-driven pathologies supporting research in mechanisms of retinal inflammation.

Recently, we have demonstrated that Adeno-associated virus (AAV)-mediated expression of human TNF-α in the murine eye induces retinal inflammation including vasculitis and fibrosis, thereby mimicking human disease-relevant pathologies. In a proof-of-mechanism study, we now tested whether AAV-TNF-α induced pathologies can be reversed by neutralizing TNF-α antibody treatment.

Inflammation is implicated in the etiology of diverse retinopathies including uveitis, age-related macular degeneration or diabetic retinopathy. Tumor necrosis factor alpha (TNF-α) is a well-known proinflammatory cytokine that is described as a biomarker for inflammation in diverse retinopathies and therefore emerged as an interesting target to treat inflammation in the eye by neutralizing anti-TNF-α antibodies.

Strikingly, a single intravitreal injection of the TNF-α antibody golimumab reduced AAV-TNF-α-induced retinal inflammation and retinal thickening. Furthermore, AAV-TNF-α-mediated impaired retinal function was partially rescued by golimumab as revealed by electroretinography recordings. Finally, to study TNF-α-induced vasculitis in human in vitro cell culture assays, we established a monocyte-to-endothelium adhesion co-culture system. Indeed, also in vitro TNF-α induced monocyte adhesion to human retinal endothelial cells, which was prevented by golimumab. Conclusions: Overall, our study describes valuable in vitro and in vivo approaches to study the function of TNF-α in retinal inflammation and demonstrated a preclinical proof-of-mechanism treatment with golimumab. Translational relevance: The AAV-based model expressing human TNF-α allows us to investigate TNF-α-driven pathologies supporting research in mechanisms of retinal inflammation.