Drs. Ishiguro and Nakamura have a patent application pending related to anti–interleukin-17A aptamers; the University of Tokyo is designated as the patent owner under Japanese government regulations.
Therapeutic potential of anti–interleukin-17A aptamer: Suppression of interleukin-17A signaling and attenuation of autoimmunity in two mouse models
Version of Record online: 28 JAN 2011
Copyright © 2011 by the American College of Rheumatology
Arthritis & Rheumatism
Volume 63, Issue 2, pages 455–466, February 2011
How to Cite
Ishiguro, A., Akiyama, T., Adachi, H., Inoue, J.-I. and Nakamura, Y. (2011), Therapeutic potential of anti–interleukin-17A aptamer: Suppression of interleukin-17A signaling and attenuation of autoimmunity in two mouse models. Arthritis & Rheumatism, 63: 455–466. doi: 10.1002/art.30108
- Issue online: 28 JAN 2011
- Version of Record online: 28 JAN 2011
- Accepted manuscript online: 21 OCT 2010 12:39PM EST
- Manuscript Accepted: 14 OCT 2010
- Manuscript Received: 19 JUN 2010
- Core Research for Evolution Science and Technology grant from the Japan Science and Technology Agency
- Ministry of Education, Sports, Culture, Science, and Technology of Japan
- Ministry of Health, Labor, and Welfare
The proinflammatory cytokine interleukin-17A (IL-17A) is produced primarily by the CD4+ T cell subset called Th17 cells, which is involved in host defense, inflammation, and autoimmune disorders. This study was undertaken to investigate the effect of a high-affinity RNA molecule, called an aptamer, against human IL-17A on IL-17A–induced signal transduction in vitro and its anti-autoimmune efficacy in vivo in 2 mouse models of inflammation.
By screening a large library of nuclease-resistant RNA oligonucleotides, we selected an RNA aptamer, Apt21-2, that binds human and mouse IL-17 and blocks the interaction between IL-17A and its receptor. The inhibition of IL-17A–mediated phosphorylation and marker protein production was analyzed in human and mouse cells. Mice with glucose-6-phosphate isomerase (GPI)–induced rheumatoid arthritis and myelin oligodendrocyte glycoprotein (MOG)–induced experimental autoimmune encephalomyelitis were used to assess efficacy.
Apt21-2 prevented efficient phosphorylation of the IL-17A signaling factors IκB and JNK and inhibited the production of IL-6 in human and mouse cells. A PEGylated form of Apt21-2 (PEG21-2idT) exhibited a 50% inhibition concentration (IC50) in the range of 1–2 nM and 70–80 nM in human and mouse cells, respectively. When administered immediately after immunization with GPI or MOG, PEG21-2idT inhibited in a dose-dependent manner the development of arthritic or neurologic symptoms. Significantly, PEG21-2idT slowed the progression of arthritis when administered after the onset of GPI-induced arthritis.
Our findings indicate that the chemically processed anti–IL-17A aptamer PEG21-2idT inhibits the actions of IL-17A as well as the development of autoimmunity in 2 mouse models of inflammation. These results offer for the first time an aptamer-based therapeutic approach to the treatment of Th17 cell–mediated autoimmune disorders.