Leptin neutralization interferes with pathogenic T cell autoreactivity in autoimmune encephalomyelitis

J Clin Invest. 2006 Feb;116(2):447-55. doi: 10.1172/JCI26523. Epub 2006 Jan 12.

Abstract

Recent evidence has indicated that leptin, an adipocyte-secreted hormone belonging to the helical cytokine family, significantly influences immune and autoimmune responses. We investigate here the mechanisms by which in vivo abrogation of leptin effects protects SJL/J mice from proteolipid protein peptide PLP(139-151)-induced EAE, an animal model of MS. Blockade of leptin with anti-leptin Abs or with a soluble mouse leptin receptor chimera (ObR:Fc), either before or after onset of EAE, improved clinical score, slowed disease progression, reduced disease relapses, inhibited PLP(139-151)-specific T cell proliferation, and switched cytokine secretion toward a Th2/regulatory profile. This was also confirmed by induction of forkhead box p3 (Foxp3) expression in CD4 T cells in leptin-neutralized mice. Importantly, anti-leptin treatment induced a failure to downmodulate the cyclin-dependent kinase inhibitor p27 (p27) in autoreactive CD4 T cells. These effects were associated with increased tyrosine phosphorylation of both ERK1/2 and STAT6. Taken together, our data provide what we believe is a new molecular basis for leptin antagonism in EAE and envision novel strategies of leptin-based molecular targeting in the disease.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies / metabolism
  • Antigens, Differentiation / metabolism
  • Cytokines / immunology
  • Disease Progression
  • Encephalomyelitis, Autoimmune, Experimental / immunology*
  • Encephalomyelitis, Autoimmune, Experimental / physiopathology
  • Female
  • Forkhead Transcription Factors / genetics
  • Forkhead Transcription Factors / metabolism
  • Humans
  • Hypersensitivity, Delayed
  • Integrin alpha4beta1 / immunology
  • Intercellular Adhesion Molecule-1 / genetics
  • Intercellular Adhesion Molecule-1 / metabolism
  • Leptin / immunology
  • Leptin / physiology*
  • Mice
  • Myelin Proteolipid Protein / immunology
  • Peptide Fragments / immunology
  • Receptors, Cell Surface / genetics
  • Receptors, Cell Surface / metabolism
  • Receptors, Leptin
  • Recombinant Fusion Proteins / genetics
  • Recombinant Fusion Proteins / metabolism
  • T-Lymphocytes / immunology*

Substances

  • Antibodies
  • Antigens, Differentiation
  • Cytokines
  • Forkhead Transcription Factors
  • Foxp3 protein, mouse
  • Integrin alpha4beta1
  • Leptin
  • Myelin Proteolipid Protein
  • OX40Ig
  • Peptide Fragments
  • Receptors, Cell Surface
  • Receptors, Leptin
  • Recombinant Fusion Proteins
  • leptin receptor, human
  • leptin receptor, mouse
  • myelin proteolipid protein (139-151)
  • Intercellular Adhesion Molecule-1