T cell lessons from the rheumatoid arthritis synovium SCID mouse model:CD3-rich synovium lacks response to CTLA-4ig but is successfully treated by interleukin-17 neutralization

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 antitumor necrosis factor (anti-TNF) and antiinterleukin-1 (antiIL-1) treatment and to investigate the direct effect of T cells and B cellrelated therapies on the transplanted RA synovial tissue. Methods CB17/SCID mice were engrafted with human RA synovial tissue and systemically treated with anti-TNF, antiIL-1, antiIL-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 antiIL-1 therapy did not show any effect on the RA synovial grafts. In mice engrafted with B cellrich 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 antiIL-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.