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T cell lessons from the RA synovium SCID mouse model: CD3 rich synovium lacks response to CTLA4-Ig but is successfully treated by IL-17 neutralization.
Abstract
OBJECTIVE: To provide an intermediate step between classical arthritis models and clinical trials, the RA synovium SCID mouse model is a valuable tool during preclinical research. In this study, the validity of this humanized mouse model was investigated using anti-TNF and anti-IL-1 treatment. In addition, the direct effect of T and B cell-related therapies on the transplanted RA synovial tissue was investigated. METHODS: SCID.CB17 mice were engrafted with human RA synovial tissue, and systemically treated with anti-TNF, anti-IL-1, anti-IL-17, CTLA4-Ig, anti-CD20, or isotype control antibodies. RESULTS: Validation of the model with anti-TNF treatment significantly reduced serum cytokine levels and decreased histological 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, CTLA4-Ig treatment did not show any effects in this transplantation model, even despite pre-screening of the synovial tissue for the presence of CD3+ T cells and the co-stimulatory molecules CD80/86. In contrast, great therapeutic potential was observed for anti-IL-17 treatment, however 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 CTLA4-Ig 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 profile is of great importance to achieve tailor-made therapy.
