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Abstract

Objective

To provide an intermediate step between classic arthritis models and clinical trials, the rheumatoid arthritis (RA) synovium SCID mouse model is a valuable tool for use during preclinical research. We undertook this study to investigate the validity of this humanized mouse model using anti–tumor necrosis factor (anti-TNF) and anti–interleukin-1 (anti–IL-1) treatment and to investigate the direct effect of T cells– and B cell–related therapies on the transplanted RA synovial tissue.

Methods

CB17/SCID mice were engrafted with human RA synovial tissue and systemically treated with anti-TNF, anti–IL-1, anti–IL-17, CTLA-4Ig, anti-CD20, or isotype control antibodies.

Results

Validation of the model with anti-TNF treatment significantly reduced serum cytokine levels and decreased histologic inflammation, whereas anti–IL-1 therapy did not show any effect on the RA synovial grafts. In mice engrafted with B cell–rich synovial tissue, anti-CD20 treatment showed clear therapeutic effects. Surprisingly, CTLA-4Ig treatment did not show any effects in this transplantation model, despite prescreening of the synovial tissue for the presence of CD3+ T cells and the costimulatory molecules CD80 and CD86. In contrast, great therapeutic potential was observed for anti–IL-17 treatment, but only when CD3+ T cells were abundantly present in the RA synovial tissue.

Conclusion

This human RA synovium SCID mouse model enabled us to show that CTLA-4Ig lacks direct effects on T cell activation processes in the synovial tissue. Further evidence was obtained that IL-17 might indeed be an interesting therapeutic target in RA patients with CD3-rich synovial tissue. Further characterization of the RA patients' individual synovial profiles is of great importance for achieving tailored therapy.