Adalimumab Reprograms M1 Macrophages to Attenuate Th1/Th17 Responses in Behçet's Uveitis and Vogt–Koyanagi–Harada Syndrome

Purpose: To investigate the effects and underlying mechanisms of adalimumab on monocyte-derived macrophage polarization and CD4+ T cell responses in patients with Behçet's uveitis (BU) or Vogt-Koyanagi-Harada (VKH) syndrome. Methods: Ex vivo analyses were performed on monocyte-derived macrophages and CD4+ T cells from patients with active BU (n = 43) and VKH (n = 35). In vivo experiments were performed using an experimental autoimmune uveitis (EAU) model. The effects of adalimumab on macrophage polarization and cytokine production were assessed using flow cytometry and enzyme-linked immunosorbent assay, respectively. The underlying adalimumab-induced immunomodulatory cascade was evaluated using coculture systems with healthy donor CD4⁺ T cells. Disease-specific mechanisms were investigated through integrated transcriptomic and proteomic profiling and validated by real-time quantitative polymerase chain reaction and western blot. Results: Proinflammatory M1 macrophage polarization was significantly enhanced in patients with BU and VKH. Adalimumab selectively suppressed M1 polarization and the production of tumor necrosis factor-alpha, IL-1β, IL-6, and IL-12. These adalimumab-reprogrammed M1 macrophages promoted CD4+ T cell apoptosis and inhibited Th1/Th17 responses. However, adalimumab did not directly affect T cells. Multi-omics analysis and validation experiments revealed disease-specific mechanisms, notably the significant downregulation of the expression of metallothionein members, including MT1H, MT1G, MT1A, MT1F, MT1E, MT1X, and MT2A, in BU and that of SLC39A8 in VKH. Furthermore, adalimumab therapy reversed the increased frequencies of CD80+ macrophages and Th1/Th17 cells in the spleen and in association with remission of uveitis in the EAU model. Conclusions: Adalimumab modulates macrophage polarization to attenuate T cell-mediated inflammation by targeting different proteins in BU and VKH, providing novel insights for precision immunotherapy in uveitis.