Open AccessT 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
Author(s) -
Koenders Marije I.,
Marijnissen Renoud J.,
Joosten Leo A. B.,
AbdollahiRoodsaz Shahla,
Di Padova Franco E.,
van de Loo Fons A.,
Dulos John,
van den Berg Wim B.,
Boots Annemieke M. H.
Publication year - 2012
Publication title -
arthritis & rheumatism
Language(s) - English
Resource type - Journals
eISSN - 1529-0131
pISSN - 0004-3591
DOI - 10.1002/art.34352
Subject(s) - medicine , immunology , t cell , arthritis , cd86 , synovial membrane , rheumatoid arthritis , cd20 , cd80 , humanized mouse , cytokine , tumor necrosis factor alpha , antibody , immune system , cytotoxic t cell , cd40 , biology , biochemistry , in vitro
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.