Anti-VISTA antibody suppresses neutrophil-mediated inflammation 2969

Abstract Description A growing body of evidence suggests that VISTA, an immune checkpoint inhibitory receptor, plays a central role in the regulation of innate immunity in the settings of inflammatory diseases. In this study, targeting VISTA on neutrophils with a monoclonal antibody (mAb) resulted in a striking reduction in their LPS-induced accumulation in spleen and blood. This was dependent on VISTA neutrophil expression as anti-VISTA mAb did not reduce LPS-stimulated peripheral neutrophil accumulation in mice conditionally deficient in neutrophil VISTA (S100a8cre Vsirfl/fl). Unlike wild-type and Fcgr2b-/- mice, Fcer1g-/- mice treated with anti-VISTA mAb showed no decrease in splenic neutrophil numbers after LPS challenge. Concomitant with reduced splenic neutrophil cell numbers, anti-VISTA treatment was associated with a 2-fold increase in SYTOX+ neutrophils in the liver. Immunofluorescent staining showed an increase in F4/80+ cells containing myeloperoxidase (MPO), suggesting neutrophil engulfment in the liver. Depletion of phagocytic macrophages with clodronate liposomes prior to LPS challenge prevented neutrophil loss with anti-VISTA treatment. The effectiveness of anti-VISTA mAb was tested in a murine model of neutrophil-mediated arthritis. Anti-VISTA treatment ameliorated disease severity, which was associated with reduced MPO activity in the joints. These studies identify a novel therapeutic opportunity for targeting VISTA to control neutrophil-mediated inflammation and tissue injury. Funding Sources This work was supported by NIH grants R01CA214062 and R01AR070760 to R.J.N. and R21AR079661-01 to S.S.G. It also received support from the 2022 LRA Lupus Innovation Award and CDMRP Lupus Research Program W81XWH2110889 to S.S.G, and NCI Cancer Center Support Grants 5P30CA023108-37 and 5P30CA023108-43. Topic Categories Therapeutic Approaches to Autoimmunity (THER)