Inhibition of T cell-mediated inflammation in uveitis by a novel anti-CD3 antibody

Abstract

BackgroundA novel anti-mouse CD3ε antibody, Dow2, recognizes mouse CD3ε without activating T cells and suppresses T-cell activation. The purpose of this study was to determine whether Dow2 can inhibit T cells in uveitis.MethodsExperimental autoimmune uveitis (EAU) was induced in mice by immunization with retinal peptides, followed by administration of Dow2. Inflammation was evaluated by color fundus photography, optical coherence tomography, fluorescein angiography, and histology. Intraocular cells from EAU mice were used to examine the effect of Dow2 on retinal antigen-specific T cells. The effects of Dow2, conventional CD3ε antibodies, and isotype control immunoglobulin G (IgG) on splenic T cells were compared by assessing cell proliferation by the mixed lymphocyte reaction assay, inflammatory cytokine production by enzyme-linked immunosorbent assay (ELISA) and immunohistochemistry, and gene expression by quantitative reverse-transcription polymerase chain reaction (RT-PCR). T-cell subpopulations were characterized by flow cytometry to evaluate the expression of CD4, CD8, CD44, CD62L, and Foxp3.ResultsDow2 significantly reduced T-cell activation and counteracted activation associated with anti-CD3ε antibodies. Unlike conventional CD3ε antibodies, Dow2 treatment did not upregulate T helper (Th)1-/Th17-associated gene expression and cytokine production in splenic T cells. Interferon (IFN)-γ production by retinal antigen-specific T cells was also significantly reduced. Ocular inflammation was significantly reduced in Dow2-treated EAU mice compared to control EAU mice, with fewer T cells infiltrating into the retinas of Dow2-treated EAU mice. In immunohistochemistry, Th1 and Th17 cells invaded the retina in control EAU mice but not Dow2-treated EAU mice. No effects on peripheral T-cell numbers were observed following systemic administration of Dow2.ConclusionThe novel anti-CD3 antibody Dow2 can inhibit T cell-mediated inflammation in uveitis models. Thus, inhibition of T-cell activation by anti-CD3 therapy with this new antibody may protect uveitis patients from severe ocular inflammation.

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