Impaired Oral Tolerance Induction in Diabetes Prone but not in Diabetes Resistant Mice Revealed by Cholera Toxin Subunit B-Peptide Fusion Proteins
| Autor: | Angela Zarama Ortiz, Nahir Garabatos, David V. Serreze, Cristina Izquierdo, Luc Teyton, Thomas Stratmann, Conchi Mora, Elisa I. Rivas, Maximiliano Presa |
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| Rok vydání: | 2013 |
| Předmět: |
CD4-Positive T-Lymphocytes
Cholera Toxin Recombinant Fusion Proteins medicine.medical_treatment Immunology Glutamate decarboxylase Administration Oral Epitopes T-Lymphocyte Nod Biology Pharmacology Lymphocyte Activation medicine.disease_cause Article Epitope Interferon-gamma Mice Adjuvants Immunologic Mice Inbred NOD Immune Tolerance medicine Oral vaccine Animals Immunology and Allergy NOD mice Type 1 diabetes Glutamate Decarboxylase Cholera toxin FOXP3 Cholera Vaccines medicine.disease Peptide Fragments Diabetes Mellitus Type 1 MHC tetramer Interleukin-4 Adjuvant |
| Zdroj: | Repositorio Abierto de la UdL Universitad de Lleida |
| Popis: | The cholera toxin B subunit (CTB) has been used as adjuvant to improve oral vaccine delivery in type 1 diabetes. The effect of CTB/peptide formulations on Ag-specific CD4+ T cells has remained largely unexplored. Here, using tetramer analysis, we investigated how oral delivery of CTB fused to two CD4+ T-cell epitopes, the BDC-2.5 T-cell 2.5mi mimotope and glutamic acid decarboxylase (GAD) 286–300, affected diabetogenic CD4+ T cells in nonobese diabetic (NOD) mice. When administered i.p., CTB-2.5mi activated 2.5mi+ T cells and following intragastric delivery generated Ag-specific Foxp3+ Treg and Th2 cells. While 2.5mi+ and GAD-specific T cells were tolerized in diabetes-resistant NODxB6.Foxp3EGFP F1 and nonobese resistant (NOR) mice, this did not occur in NOD mice. This indicated that NOD mice had a recessive genetic resistance to induce oral tolerance to both CTB-fused epitopes. In contrast to NODxB6.Foxp3EGFP F1 mice, oral treatment in NOD mice lead to strong 2.5mi+ T-cell activation and the sequestration of these cells to the effector-memory pool. Oral treatment of NOD mice with CTB-2.5mi failed to prevent diabetes. These findings underline the importance of investigating the effect of oral vaccine formulations on diabetogenic T cells as in selected cases they may have counterproductive consequences in human patients. This work was supported by grants from the Spanish Ministry of Science and Innovation and European Regional Development Fund (FEDER; SAF2004- 02666, SAF2007-65291, SAF2010-18548, SAF2011-29319 to T.S.; SAF2007-31050E and SAF2008-02536 to C.M.), from the Spanish Ministry of Health and Consumption (PI040587 to T.S. and P041310 to C.M.), and from the European Community (MIRG-CT-2004-012692 to T.S.). T.S. was also supported by the Ramon y Cajal program from the Spanish Ministry of Science and ´ Innovation. D.S. is supported by NIH grants DK46266, DK97610, DK72473, as well as by grants from the Juvenile Diabetes Research Foundation and the American Diabetes Association. |
| Databáze: | OpenAIRE |
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