Arthritis & Rheumatism, Volume 62,
November 2010 Abstract Supplement
Abstracts of the American College of
Rheumatology/Association of Rheumatology Health Professionals
Annual Scientific Meeting
Atlanta, Georgia November 6-11, 2010.
Targets of Innate and Adaptive Immunity in a Humanized Arthritis Model: Research Value of the RA Synovium SCID Mouse Model.
Koenders3, Marije I., Abdollahi-Roodsaz4, Shahla, Marijnissen4, Renoud J., Di Padova2, Franco E., Dulos1, John, Boots1, Annemieke M. H., van den Berg4, Wim B.
Target discovery and drug development is a very time consuming and expensive process, which is partly due to the fact that preclinical findings from animal models cannot always be translated to the clinical situation. To provide an intermediate step between classical arthritis models and clinical trials, the RA synovium SCID mouse model could be a valuable tool during preclinical research. In this study, the validity of this humanized mouse model was investigated.
SCID.CB17 mice were engrafted with two standardized pieces of human RA synovial tissue subcutaneously on the back, and subsequently the therapeutic effect of various biologicals on these grafts was assessed. After an engraftment period of seven days, mice were systemically treated with anti-TNF (Abalimumab), anti-IL-1, CTLA4-Ig (Abatacept), anti-CD20 (Rituximab), or isotype control antibodies at an excess dose of 10 mg/kg. In addition, this RA SCID model was used to study two new potential therapeutic targets, using the TLR4 antagonist B. quintana LPS, and anti-hIL-17A antibodies. As readout, serum levels of human cytokines and chemokines were analyzed by Luminex, and the synovial grafts were isolated for histological analysis.
Anti-TNF treatment significantly reduced serum levels of IL-6 and IL-8, and histological analysis demonstrated that this coincided with a clear reduction in the inflammation scores of the grafts and suppressed expression of TNF and IL-1 in the synovium as demonstrated by immunohistochemistry. In contrast, anti-IL-1 therapy did not show any effect. Since Adalimumab also shows great efficacy in the clinics, anti-TNF antibodies were used as positive control throughout our further SCID studies.
The potential of the RA SCID model for T and B cell-related therapies was investigated using CTLA4-Ig and anti-CD20 respectively. Abatacept treatment was not effective in this RA SCID model, despite pre-screening of the synovial tissue for the presence of CD3+ T cells and the B7 molecules CD80/86 that provide costimulatory signals for T cell activation. In contrast, anti-CD20 treatment did reduce serum cytokines and histological scores, suggesting that this model is more sensitive to B cell than T cell-related therapies.
Our recent studies in IL-1Ra-deficient mice and collagen-induced arthritis suggested an important role for TLR4 in recognition of both exogenous and endogenous ligands that contribute to the pathological process during arthritis. Also for anti-IL-17 treatment great therapeutic potential was observed in mice, but additional proof was needed in more translational models. While our TLR4 inhibitor showed therapeutic effects comparable to anti-TNF treatment, IL-17 blocking seemed to be selectively effective in cases where high numbers of CD3+ T cells were present in the synovium.
In conclusion, the human RA synovium SCID mouse model seems a powerful tool in preclinical research. Using this model, further evidence was obtained that TLR4 and IL-17 might indeed be interesting therapeutic targets in RA. Further characterization of the RA patients' individual synovial profile is of great importance to achieve tailor-made therapy.
To cite this abstract, please use the following information:
Koenders, Marije I., Abdollahi-Roodsaz, Shahla, Marijnissen, Renoud J., Di Padova, Franco E., Dulos, John, Boots, Annemieke M. H., et al; Targets of Innate and Adaptive Immunity in a Humanized Arthritis Model: Research Value of the RA Synovium SCID Mouse Model. [abstract]. Arthritis Rheum 2010;62 Suppl 10 :1730