Short Duration Alagebrium Chloride Therapy Prediabetes Does Not Inhibit Progression to Autoimmune Diabetes in an Experimental Model
| Autor: | Anthony W. Purcell, Casper G. Schalkwijk, Rochelle Ayala, David Briskey, Jean L.J.M. Scheijen, Josephine M. Forbes, Raymond J. Steptoe, Kai Lin Giam, Sherman Leung, Domenica A. McCarthy, Brooke E. Harcourt, Micheal S. Ward, Peta L. S. Reeves, Amelia K. Fotheringham, Pouya Faridi, Danielle J. Borg, Nadine L. Dudek |
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| Přispěvatelé: | MUMC+: MA Alg Onderzoek Interne Geneeskunde (9), Interne Geneeskunde, RS: Carim - V01 Vascular complications of diabetes and metabolic syndrome, MUMC+: MA Alg Interne Geneeskunde (9) |
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
0301 basic medicine
EXPRESSION medicine.medical_specialty immunopeptidome type 1 diabetes Endocrinology Diabetes and Metabolism cross-link breaker 030209 endocrinology & metabolism MIN6N8 cell line Major histocompatibility complex Microbiology Biochemistry INSULIN-SECRETION DENDRITIC CELLS autoimmune diabetes Article 03 medical and health sciences 0302 clinical medicine Immune system Antigen Internal medicine MHC class I medicine Prediabetes Molecular Biology TYPE-1 Type 1 diabetes LYMPH-NODES biology RECEPTOR business.industry advanced glycation end products medicine.disease QR1-502 RAGE 3. Good health 030104 developmental biology Endocrinology biology.protein T-CELLS business GLYCATION END-PRODUCTS Insulitis alagebrium chloride CD8 BETA-CELL DYSFUNCTION NOD mouse |
| Zdroj: | Metabolites Volume 11 Issue 7 Metabolites, Vol 11, Iss 426, p 426 (2021) Metabolites, 11(7):426. Multidisciplinary Digital Publishing Institute (MDPI) |
| ISSN: | 2218-1989 |
| Popis: | Mechanisms by which advanced glycation end products (AGEs) contribute to type 1 diabetes (T1D) pathogenesis are poorly understood. Since life-long pharmacotherapy with alagebrium chloride (ALT) slows progression to experimental T1D, we hypothesized that acute ALT therapy delivered prediabetes, may be effective. However, in female, non-obese diabetic (NODShiLt) mice, ALT administered prediabetes (day 50–100) did not protect against experimental T1D. ALT did not decrease circulating AGEs or their precursors. Despite this, pancreatic β-cell function was improved, and insulitis and pancreatic CD45.1+ cell infiltration was reduced. Lymphoid tissues were unaffected. ALT pre-treatment, prior to transfer of primed GC98 CD8+ T cell receptor transgenic T cells, reduced blood glucose concentrations and delayed diabetes, suggesting islet effects rather than immune modulation by ALT. Indeed, ALT did not reduce interferon-γ production by leukocytes from ovalbumin-pre-immunised NODShiLt mice and NODscid recipients given diabetogenic ALT treated NOD splenocytes were not protected against T1D. To elucidate β-cell effects, NOD-derived MIN6N8 β-cell major histocompatibility complex (MHC) Class Ia surface antigens were examined using immunopeptidomics. Overall, no major changes in the immunopeptidome were observed during the various treatments with all peptides exhibiting allele specific consensus binding motifs. As expected, longer MHC Class Ia peptides were captured bound to H-2Db than H-2Kb under all conditions. Moreover, more 10–12 mer peptides were isolated from H-2Db after AGE modified bovine serum albumin (AGE-BSA) treatment, compared with bovine serum albumin (BSA) or AGE-BSA+ALT treatment. Proteomics of MIN6N8 cells showed enrichment of processes associated with catabolism, the immune system, cell cycling and presynaptic endocytosis with AGE-BSA compared with BSA treatments. These data show that short-term ALT intervention, given prediabetes, does not arrest experimental T1D but transiently impacts β-cell function. |
| Databáze: | OpenAIRE |
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