An analysis of single-cell data reveals therapeutic effects of AMG487 in experimental autoimmune uveitis

Abstract

Uveitis, an ocular autoimmune disease that poses a significant threat to vision, is caused by immune cells erroneously attacking retinal cells and currently lacks specific and effective therapeutic interventions. The CXC chemokine receptor 3 (CXCR3) facilitates the migration of immune cells to sites of inflammation. AMG487, a CXCR3 antagonist, holds potential for treating autoimmune diseases by blocking immunes cells chemotaxis. However, its effects and mechanisms in uveitis remain unclear. Using single-cell assay for transposase-accessible chromatin sequencing and RNA sequencing, we observed increased expression of CXCR3 and chemotactic pathways in peripheral blood of Vogt-Koyanagi-Harada patients and cervical lymph nodes of experimental autoimmune uveitis mice. AMG487 treatment in experimental autoimmune uveitis was shown to be therapeutically effective. Analysis of flow cytometry and single-cell RNA sequencing in AMG487-treated mice revealed reduced expression of inflammatory genes in immune cells. Specifically, AMG487 decreased the proportion of plasma cell in B cells, restored the ratio between effector T cells and regulatory T cells, and diminished T helper (Th) 17 cell pathogenicity by suppressing highly inflammatory granulocyte–macrophage colony-stimulating factor-producing Th17 cells while enhancing anti-inflammatory interleukin-10-producing Th17 cells. Our study presents an exhaustive single-cell transcriptional analysis of immune cells under AMG487 treatment, thereby elucidating potential mechanisms and providing a potential reference for the development of novel therapeutic strategies for autoimmune diseases.