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.

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.

DOI: 10.1016/j.molimm.2009.05.007

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@article{Bhm2009ProteaseresistantHG, title={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.}, author={Bernhard B{\"{o}hm and Silke Rosinger and Guido Sauer and Burkhard J. Manfras and David Palesch and Stefan Schiekofer and Hubert Kalbacher and Timo Burster}, journal={Molecular immunology}, year={2009}, volume={46 13}, pages={2576-84} }