Protease-resistant human GAD-derived altered peptide ligands decrease TNF-alpha and IL-17 production in peripheral blood cells from patients with type 1 diabetes mellitus

Bernhard O Boehm, Silke Rosinger, Guido Sauer, Burkhard J Manfras, David Palesch, Stefan Schiekofer, Hubert Kalbacher, Timo Burster

Research output: Contribution to journalArticle

18 Citations (Scopus)

Abstract

Glutamic acid decarboxylase 65 (GAD) and proinsulin are major diabetes-associated autoantigens that drive autoreactive T cells. Altered peptide ligands (APL) have been proposed as reagents for the modification of autoimmune reactions. Here, we have prepared GAD-derived protease-resistant APL (prAPL) by cleavage site-directed modification. The resulting prAPL are resistant to lysosomal and serum proteases, bind with high-affinity to HLA-DRB1(*)0401 and have a prolonged half-life in the serum. GAD-derived prAPL significantly decreased the secretion of proinflammatory cytokines by a GAD-specific human T cell clone. Likewise, the production of IL-17, TNF-alpha, and secretion of IL-6 by peripheral blood lymphocytes from patients with type 1 diabetes mellitus (T1D) was reduced, when stimulated with both GAD and GAD-derived prAPL. Thus, prAPL with high affinity for HLA-DRB1(*)0401 mitigate the response of GAD-reactive human Th17 cells. The strategy of designing specific immunomodulatory protease-resistant altered peptide ligands provides the basis for novel avenues of therapeutic intervention.

Original languageEnglish
Pages (from-to)2576-84
Number of pages9
JournalMolecular Immunology
Volume46
Issue number13
DOIs
Publication statusPublished - Aug 2009

Keywords

  • Cathepsins
  • Cell Line
  • Chromatography, High Pressure Liquid
  • Diabetes Mellitus, Type 1
  • Dose-Response Relationship, Drug
  • Enzyme-Linked Immunosorbent Assay
  • Glutamate Decarboxylase
  • Humans
  • Interleukin-2
  • Interleukin-6
  • Interleukin-7
  • Leukocytes, Mononuclear
  • Mass Spectrometry
  • Peptide Fragments
  • Peptide Hydrolases
  • T-Lymphocytes
  • Tumor Necrosis Factor-alpha
  • Journal Article
  • Research Support, Non-U.S. Gov't

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