Inhibition of midkine alleviates experimental autoimmune encephalomyelitis through the expansion of regulatory T cell population

doi:10.1073/pnas.0709592105

Inhibition of midkine alleviates experimental autoimmune encephalomyelitis through the expansion of regulatory T cell population

*Department of Neuroimmunology, Research Institute of Environmental Medicine, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8601, Japan;
^‡RIBOMIC, Inc., 3-15-5-601 Shirokanedai, Minato-ku, Tokyo 108-0071, Japan;
^§Department of Basic Medical Sciences, Institute of Medical Science, University of Tokyo, Shirokanedai, Minato-ku, Tokyo 108-8639, Japan;
^¶Core Research Evolutional Science and Technology, Japan Science and Technology Agency, Toyonaka, Osaka 560-8531, Japan;
^‖Department of Bioregulation, Mie University Graduate School of Medicine, Tsu, Mie 514-8507, Japan;
**Department of Biochemistry, Nagoya University Graduate School of Medicine, Tsurumai-cho, Showa-ku, Nagoya 466-8550, Japan; and
^††Department of Health Science, Faculty of Psychological and Physical Sciences, Aichi Gakuin University, Nisshin, Aichi 470-0195, Japan

Edited by Ethan Shevach, National Institutes of Health, Bethesda, MD, and accepted by the Editorial Board January 20, 2008 (received for review October 12, 2007)

Abstract

CD4⁺CD25⁺ regulatory T (Treg) cells are crucial mediators of autoimmune tolerance. The factors that regulate Treg cells, however, are largely unknown. Here, we show that deficiency in midkine (MK), a heparin-binding growth factor involved in oncogenesis, inflammation, and tissue repair, attenuated experimental autoimmune encephalomyelitis (EAE) because of an expansion of the Treg cell population in peripheral lymph nodes and decreased numbers of autoreactive T-helper type 1 (T_H1) and T_H17 cells. MK decreased the Treg cell population ex vivo in a dose-dependent manner by suppression of STAT5 phosphorylation that is essential for Foxp3 expression. Moreover, administration of anti-MK RNA aptamers significantly expanded the Treg cell population and alleviated EAE symptoms. These observations indicate that MK serves as a critical suppressor of Treg cell expansion, and inhibition of MK using RNA aptamers may provide an effective therapeutic strategy against autoimmune diseases, including multiple sclerosis.

Footnotes

^†To whom correspondence may be addressed. E-mail: htake{at}riem.nagoya-u.ac.jp or suzumura{at}riem.nagoya-u.ac.jp
Author contributions: J.W., H.T., and Y.S. contributed equally to this work; H.T. and A.S. designed research; J.W., H.T., Y.S., S.J., T.M., and T.K. performed research; S.M., M.F., Y.N., H.M., and T.M. contributed new reagents/analytic tools; J.W., H.T., and Y.S. analyzed data; and H.T. and A.S. wrote the paper.
The authors declare no conflict of interest.
This article is a PNAS Direct Submission. E.S. is a guest editor invited by the Editorial Board.
This article contains supporting information online at www.pnas.org/cgi/content/full/0709592105/DC1.
Freely available online through the PNAS open access option.