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

Proc Natl Acad Sci U S A. 2008 Mar 11;105(10):3915-20. doi: 10.1073/pnas.0709592105. Epub 2008 Mar 4.


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(H)1) and T(H)17 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Aptamers, Nucleotide / pharmacology
  • CD4 Antigens / immunology
  • Cell Proliferation / drug effects
  • Cytokines / deficiency*
  • Cytokines / metabolism
  • Encephalomyelitis, Autoimmune, Experimental / pathology
  • Encephalomyelitis, Autoimmune, Experimental / prevention & control*
  • Forkhead Transcription Factors / immunology
  • Interleukin-2 Receptor alpha Subunit / immunology
  • Lymph Nodes / drug effects
  • Lymph Nodes / pathology
  • Mice
  • Mice, Inbred C57BL
  • Midkine
  • Myelin Proteins
  • Myelin-Associated Glycoprotein
  • Myelin-Oligodendrocyte Glycoprotein
  • Signal Transduction / drug effects
  • T-Lymphocytes, Helper-Inducer / cytology
  • T-Lymphocytes, Helper-Inducer / drug effects
  • T-Lymphocytes, Helper-Inducer / immunology
  • T-Lymphocytes, Regulatory / cytology*
  • T-Lymphocytes, Regulatory / drug effects
  • T-Lymphocytes, Regulatory / immunology*


  • Aptamers, Nucleotide
  • CD4 Antigens
  • Cytokines
  • Forkhead Transcription Factors
  • Interleukin-2 Receptor alpha Subunit
  • Mog protein, mouse
  • Myelin Proteins
  • Myelin-Associated Glycoprotein
  • Myelin-Oligodendrocyte Glycoprotein
  • Midkine