Reduction of Cell Surface T-Cell Receptor by Non-Mitogenic CD3 Antibody to Mitigate Murine Lupus

T-cells are critically involved in the pathogenesis of systemic lupus erythematosus. Although treatment with the anti-CD3 antibody has been reported to be effective in several autoimmune disease animal models including lupus, the immunosuppressive mechanisms remain obscure because of its pleiotropic kinetics. In this study, a conventional anti-CD3 (2C11C) and a non-mitogenic anti-CD3 with a manipulated Fc region (2C11S) were compared to elucidate the underlying mechanism of action. The efficacy and safety of 2C11S were demonstrated by sustained TCR reduction for a longer period as compared to 2C11C and no induction of cytokine release or T-cell depletion. Anti-CD3s were administered to NZB/W F1 (BWF1) mice at different time points for individual periods. The short-term treatment with 2C11S in the early phase of lupus suppressed the autoantibody associated with the reduction of germinal center B-cells. Treatment in the late phase attenuated lupus nephritis without affecting autoantibodies or differentiation of effector T-cells. The effect of reduced TCR in the development of autoimmunity was examined by CD3ζ heterozygous-deficient mice, in which T-cells had reduced TCR intensity but showed normal TCR signaling response. Autoantibody and lupus nephritis were attenuated significantly in CD3ζ heterozygous-deficient lupus-prone mice. Collectively, the reduction of surface TCR by non-mitogenic anti-CD3 could sufficiently suppress the development of lupus.