Recently, a number of biologics have been used in the treatment of
autoimmune diseases. However, in the treatment of severe autoimmune
uveitis, only
TNF-alpha inhibitors are preferably used and the effect of other biologics such as
interleukin-6 (IL-6) signaling blockade or cytotoxic T-lymphocyte antigen-4-immunoglobulin fusion
protein (CTLA4-Ig) has not been well studied. Previously, we reported that
IL-6 blockade effectively suppresses the development of experimental autoimmune
uveitis (EAU), a mouse model for
uveitis, by inhibiting Th17 cell development. In this study, we investigated the effect of
CTLA4-Ig on EAU development and compared it with the effect of anti-IL-6 receptor
monoclonal antibody (MR16-1). C57BL/6J mice were immunized with
interphotoreceptor retinoid-binding protein (IRBP) and treated once with
CTLA4-Ig or MR16-1. Both
CTLA4-Ig and MR16-1 administered in the induction phase (the same day as immunization) significantly reduced the clinical and histopathological scores of EAU. Fluorescence-activated cell sorting studies using draining lymph node (LN) cells from EAU mice 10 days after immunization showed that
CTLA4-Ig can suppress early T-helper cell activation.
CTLA4-Ig administered in the effector phase of the disease (one week after immunization), when IRBP-reactive T cells have been primed, also significantly reduced the clinical and histopathological scores of EAU. In contrast, MR16-1 administered in the effector phase did not ameliorate EAU. To investigate the differences between these biologics in the effector phase, in vitro restimulation analysis of LN cells obtained from EAU mice one week after immunization was performed and revealed that
CTLA4-Ig, but not MR16-1, added to
culture media could inhibit the proliferation of IRBP-specific CD4(+) T cells which possessed capacities of producing IFN-gamma and/or
IL-17. Collectively,
CTLA4-Ig ameliorated EAU through preventing initial T-cell activation in the induction phase and suppressing proliferation of IRBP-specific T cells in the effector phase. Blockade of
IL-6 signaling did not have such inhibitory effects after T-cell priming.
CTLA4-Ig may have
therapeutic effects on human chronic
uveitis.