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Abstract: PO1774

Efficacy and Safety of Non-Mitogenic Anti-CD3 in the Treatment of Lupus-Prone Mice

Session Information

Category: Glomerular Diseases

  • 1202 Glomerular Diseases: Immunology and Inflammation

Authors

  • Morita, Masashi, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
  • Mizui, Masayuki, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
  • Masuyama, Satoshi, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
  • Isaka, Yoshitaka, Osaka University Graduate School of Medicine, Suita, Osaka, Japan
Background

Armenian hamster anti-mouse CD3ε monoclonal antibody (145-2C11) is known to suppress T cell function in vivo by reducing T-cell receptor (TCR) expression and inducing T cell depletion. However, it has also mitogenic potentials through the functional Fc portion. Although in vivo administration of Fc-deleted 145-2C11 F(ab’)2 was reported to ameliorate lupus in mice, the detailed mechanisms are still unclear. Recently developed Fc-modified 145-2C11 (2C11 silent; 2C11S), which lacks the ability to bind complement or Fc receptor, is expected to be stable and safe in vivo as compared with native 145-2C11 (2C11N). Whether 2C11S has therapeutic potential in lupus remains to be elucidated.

Methods

Twenty micrograms of Armenian hamster anti-CD3ε (hamster 2C11N), mouse anti-CD3ε (mouse 2C11N), mouse anti-CD3ε Fc-silent (2C11S), or isotype control IgG1κ (IC) were injected intraperitoneally to C57BL6 mice. Lymphocyte number, TCR expression and plasma cytokines from peripheral blood were checked in time series. Next, 2C11S, 2C11N, and IC were administered (100 μg / week, 4 times, intraperitoneally) to NZB/W F1 mice at the age of 10 (early phase) and 20 (active phase) weeks, respectively. Renal histology, immune cell infiltration, and gene expression of cytokines/chemokines were evaluated.

Results

As compared with 2C11N, 2C11S reduced TCR expression on T cells in vivo for longer period (more than 96 hours) without inducing cytokine release. In early phase of lupus, the rate of change in anti-dsDNA IgG titers (day28 / day0) were significantly reduced in 2C11S group (IC; 2.9±2.0, 2C11S; 2.1±3.0, 2C11N; 2.0±1.8, IC vs 2C11S; p=0.03), which was associated with the decreased number of both follicular helper-T cells and germinal center B-cells in spleen. In active phase, glomerular hypercellularity was diminished in 2C11S group (glomerular cell number: IC; 53±18, 2C11S; 44±6.1, 2C11N; 47±6.6, IC vs 2C11S; p=0.03) and lymphocyte infiltration into kidney was significantly reduced in 2C11S group. In addition, reduction of inflammation-related genes such as IFNγ and IL-2 in kidney indicated improvement of lupus nephritis by 2C11S.

Conclusion

2C11S, but not 2C11N, suppressed autoantibody production and ameliorated lupus nephritis, possibly through stable down-regulation of TCR. Targeting CD3 to modulate TCR expression could be a novel therapeutic approach in lupus.