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
Version of Record online: 25 MAY 2012
Copyright © 2012 by the American College of Rheumatology
Arthritis & Rheumatism
Volume 64, Issue 6, pages 1762–1770, June 2012
How to Cite
Koenders, M. I., Marijnissen, R. J., Joosten, L. A. B., Abdollahi-Roodsaz, S., Di Padova, F. E., van de Loo, F. A., Dulos, J., van den Berg, W. B. and Boots, A. M. H. (2012), 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. Arthritis & Rheumatism, 64: 1762–1770. doi: 10.1002/art.34352
- Issue online: 25 MAY 2012
- Version of Record online: 25 MAY 2012
- Accepted manuscript online: 27 DEC 2011 02:58PM EST
- Manuscript Accepted: 15 DEC 2011
- Manuscript Received: 14 APR 2011
- Stichting De Drie Lichten
- Organon NV, a subsidiary of MSD, Oss, The Netherlands
- Innovative Medicines Initiative Joint Undertaking–funded project BTCure. Grant Number: Agreement 115142-2
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.
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.
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.
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.