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 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.


CONCLUSIONS
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.
Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands.
Marije I
MI
Koenders
Renoud J
RJ
Marijnissen
Leo A B
LA
Joosten
Shahla
S
Abdollahi-Roodsaz
Franco E
FE
Di Padova
Fons A
FA
van de Loo
John
J
Dulos
Wim B
WB
van den Berg
Annemieke M H
AM
Boots
D000069594:Abatacept; D000818:Animals; D057134:Antibodies, Neutralizing; D018501:Antirheumatic Agents / Q000494:pharmacology*; D001172:Arthritis, Rheumatoid / Q000188:drug therapy* / Q000276:immunology; D017252:CD3 Complex / Q000276:immunology*; D005260:Female; D018796:Immunoconjugates / Q000494:pharmacology*; D020381:Interleukin-17 / Q000037:antagonists & inhibitors*; D051379:Mice; D013583:Synovial Membrane / Q000187:drug effects* / Q000276:immunology; D013601:T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors
D057134:Antibodies, Neutralizing; D018501:Antirheumatic Agents; D017252:CD3 Complex; D018796:Immunoconjugates; D020381:Interleukin-17; D014409:Tumor Necrosis Factor-alpha; D000069594:Abatacept