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

被引：22

作者：

Boehm, Bernhard O. ^{[2
]}

Rosinger, Silke ^{[2
]}

Sauer, Guido ^{[3
]}

Manfras, Burkhard J. ^{[2
]}

Palesch, David ^{[2
]}

Schiekofer, Stefan ^{[2
]}

Kalbacher, Hubert ^{[4
]}

Burster, Timo ^{[1
,2
]}

机构：

[1] Univ Med Ctr Ulm, Div Endocrinol & Diabet, Ctr Internal Med, Dept Internal Med 1, D-89081 Ulm, Germany

[2] Ctr Excellence Metab Disorders, D-89081 Ulm, Germany

[3] Max Planck Inst Dev Biol, Tubingen, Germany

[4] Univ Tubingen, Med & Nat Sci Res Ctr, D-72074 Tubingen, Germany

来源：

MOLECULAR IMMUNOLOGY | 2009年 / 46卷 / 13期

关键词：

Diabetes; Antigen presentation/processing; Cathepsin; Altered peptide ligands; GAD65; GLUTAMIC-ACID DECARBOXYLASE; MYELIN BASIC-PROTEIN; INHIBIT ANTIGEN PRESENTATION; MULTIPLE-SCLEROSIS; T-CELLS; AUTOIMMUNE ENCEPHALOMYELITIS; CYSTEINE PROTEASES; IMMUNE-RESPONSE; CATHEPSIN-G; MHC;

D O I：

10.1016/j.molimm.2009.05.007

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

070307 [化学生物学]; 071010 [生物化学与分子生物学];

摘要：

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 I 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. (C) 2009 Elsevier Ltd. All rights reserved.

引用

页码：2576 / 2584

页数：9

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