Purpose
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.
Methods
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.
Results
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.