Abstract
Purpose :
This investigation seeks to unravel the effects of upadacitinib, a selective JAK1 inhibitor, on non-infectious uveitis, with a focus on delineating its molecular action mechanisms.
Methods :
We employed single-cell RNA and assay for transposase-accessible chromatin sequencing to scrutinize the JAK-STAT pathway in non-infectious uveitis patients and experimental autoimmune uveitis (EAU). Our analysis integrated gene expression and cellular communication, validated by flow cytometry and western blotting. We also explored upadacitinib's therapeutic effects on two individuals with refractory uveitis.
Results :
Enhanced activity of the JAK-STAT pathway was observed in both patient and EAU model. Upadacitinib effectively mitigated EAU symptoms, reduced JAK1 protein levels, and subdued the proliferation and pathogenic behavior of CD4 T cells, while fostering the regulatory T cells (Tregs). Furthermore, Upadacitinib restored the balance in the interferon-stimulated gene 15 (ISG15)+ CD4 and CD8 T cells and B cells, and diminished the expression of genes linked to inflammation. Its role in impeding abnormal cell communication, especially in the CXCR4-mediated migration pathway, was notable. Consistently, CXCR4 inhibitors showed promising therapeutic effects in EAU. In cases of refractory uveitis, Upadacitinib improved visual acuity and effectively controlled intraocular inflammation.
Conclusions :
Our research delineate that the JAK-STAT pathway is significantly upregulated in uveitis with upadacitinib demonstrating substantial therapeutic effectiveness in EAU. Additionally, the strategy of targeting the CXCR4-mediated migration pathway presents itself as a promising approach. Furthermore, Upadacitinib could be considered a promising therapeutic strategy for managing recalcitrant cases of uveitis.
This abstract was presented at the 2024 ARVO Annual Meeting, held in Seattle, WA, May 5-9, 2024.