[This corrects the article DOI: 10.1155/2016/2424306.].

• Publikační typ
• tisková chyba MeSH

Tolerogenic dendritic cells (tolDCs) may offer an interesting intervention strategy to re-establish Ag-specific tolerance in autoimmune diseases, including type 1 diabetes (T1D). T1D results from selective destruction of insulin-producing β cells leading to hyperglycemia that, in turn, specifically affects a patient's immune system. In this study, we prepared monocyte-derived tolDCs modulated by dexamethasone and vitamin D2 from 31 T1D patients with optimal glycemic control and 60 T1D patients with suboptimal glycemic control and assessed their tolerogenic properties in correlation with metabolic state of patients. tolDCs differentiated from both groups of patients acquired a regulatory phenotype and an anti-inflammatory profile. Interestingly, tolDCs from well-controlled patients expressed higher levels of inhibitory molecules IL-T3 and PD-L1. Additionally, glutamic acid decarboxylase (GAD)65-loaded tolDCs from well-controlled patients decreased significantly primary Th1/Th17 responses, induced stable GAD65-specific T cell hyporesponsiveness, and suppressed markedly control DC-induced GAD65-specific T cell activation compared with poorly controlled patients. The ability of tolDCs from poorly controlled patients to induce durable GAD65-specific T cell hyporesponsiveness was reversed once the control of glycemia improved. In both groups of patients, tolDCs were able to induce regulatory T cells from autologous naive CD4+ T cells. However, regulatory T cells from well-controlled patients had better suppressive abilities. The functionality of tolDCs was confirmed in the adoptive transfer model of NOD-SCID mice where tolDCs delayed diabetes onset. These results suggest that metabolic control of T1D affects the functional characteristics of tolDCs and subsequent effector T cell responses. Metabolic control may be relevant for refining inclusion criteria of clinical trials in the settings of T1D.

• MeSH
• aktivace lymfocytů imunologie   MeSH
• dendritické buňky imunologie   MeSH
• diabetes mellitus 1. typu imunologie   MeSH
• imunologická tolerance imunologie   MeSH
• lidé MeSH
• myši inbrední NOD MeSH
• myši SCID MeSH
• myši MeSH
• převzatá imunita MeSH
• průtoková cytometrie MeSH
• regulační T-lymfocyty imunologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Gluten promotes type 1 diabetes in nonobese diabetic (NOD) mice and likely also in humans. In NOD mice and in non-diabetes-prone mice, it induces inflammation in the pancreatic lymph nodes, suggesting that gluten can initiate inflammation locally. Further, gliadin fragments stimulate insulin secretion from beta cells directly. We hypothesized that gluten fragments may cross the intestinal barrier to be distributed to organs other than the gut. If present in pancreas, gliadin could interact directly with the immune system and the beta cells to initiate diabetes development. We orally and intravenously administered 33-mer and 19-mer gliadin peptide to NOD, BALB/c, and C57BL/6 mice and found that the peptides readily crossed the intestinal barrier in all strains. Several degradation products were found in the pancreas by mass spectroscopy. Notably, the exocrine pancreas incorporated large amounts of radioactive label shortly after administration of the peptides. The study demonstrates that, even in normal animals, large gliadin fragments can reach the pancreas. If applicable to humans, the increased gut permeability in prediabetes and type 1 diabetes patients could expose beta cells directly to gliadin fragments. Here they could initiate inflammation and induce beta cell stress and thus contribute to the development of type 1 diabetes.

• MeSH
• aplikace orální MeSH
• beta-buňky imunologie   metabolismus   MeSH
• chromatografie kapalinová MeSH
• diabetes mellitus 1. typu imunologie   MeSH
• elektroforéza v polyakrylamidovém gelu MeSH
• gliadin imunologie   farmakokinetika   MeSH
• hmotnostní spektrometrie MeSH
• inzulin metabolismus   MeSH
• myši inbrední BALB C MeSH
• myši inbrední C57BL MeSH
• myši inbrední NOD MeSH
• pankreas exokrinní metabolismus   MeSH
• pankreas metabolismus   MeSH
• peptidové fragmenty farmakokinetika   MeSH
• permeabilita MeSH
• sekrece inzulinu MeSH
• spektrometrie hmotnostní - ionizace laserem za účasti matrice MeSH
• střevní sliznice metabolismus   MeSH
• zánět MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• gliadin MeSH
• inzulin MeSH
• peptidové fragmenty MeSH

Studies have documented that the pathogenesis of autoimmune diabetes is influenced by the intake of gluten. Aims. To investigate the importance of gluten exposure during pregnancy and the subsequent development of autoimmune diabetes in offspring. Methods. Nonobese diabetic mice were divided into 7 groups to receive combinations of gluten-free and standard diet before, during, or after pregnancy. Diabetes incidence in offspring was followed in each group (n = 16-27) for 310 days. Insulitis score and intestinal expression of T-cell transcription factors (RT-QPCR) were evaluated in animals from the different diet groups. Results. If mothers were fed a gluten-free diet only during pregnancy, the development of autoimmune diabetes in offspring was almost completely prevented with an incidence reduction from 62.5% in gluten-consuming mice to 8.3% (p < 0.0001) in the gluten-free group. The islets of Langerhans were less infiltrated (p < 0.001) and the intestinal expression of RORγt (Th17) (p < 0.0001) reduced in mice whose mothers were Gluten-free during pregnancy. Conclusion. A gluten-free diet exclusively during pregnancy efficiently prevents autoimmune diabetes development in offspring and reduces insulitis and intestinal expression of RORγt (Th17).

• MeSH
• bezlepková dieta metody   MeSH
• diabetes mellitus 1. typu dietoterapie   imunologie   prevence a kontrola   MeSH
• jaderné receptory - podrodina 1, skupina F, člen 3 genetika   MeSH
• Langerhansovy ostrůvky imunologie   patologie   MeSH
• messenger RNA metabolismus   MeSH
• myši inbrední NOD MeSH
• myši MeSH
• pankreatitida imunologie   patologie   MeSH
• polymerázová řetězová reakce s reverzní transkripcí MeSH
• střevní sliznice metabolismus   MeSH
• těhotenství při diabetu dietoterapie   MeSH
• těhotenství MeSH
• transkripční faktory TCF genetika   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• těhotenství MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• jaderné receptory - podrodina 1, skupina F, člen 3 MeSH
• messenger RNA MeSH
• transkripční faktory TCF MeSH

Induction of long-term tolerance to β-cell autoantigens has been investigated both in animal models and in human type 1 diabetes (T1D) in order to prevent the disease. As regards external compounds, the dietary plant protein fraction has been associated with high penetrance of the disease, whereas gluten-free diets prevent T1D in animal models. Herewith we investigated whether intranasal (i.n.) administration of gliadin or gluten may arrest the diabetogenic process. I.n. administration of gliadin to 4-week-old NOD mice significantly reduced the diabetes incidence. Similarly, the insulitis was lowered. Intranasal gliadin also rescued a fraction of prediabetic 13-week-old NOD mice from progressing to clinical onset of diabetes compared to OVA-treated controls. Vaccination with i.n. gliadin led to an induction of CD4(+)Foxp3(+) T cells and even more significant induction of γδ T cells in mucosal, but not in non-mucosal lymphoid compartments. This prevention strategy was characterized by an increased proportion of IL-10 and a decreased proportion of IL-2, IL-4 and IFN-γ-positive CD4(+)Foxp3(+) T cells, and IFN-γ-positive γδ T cells, preferentially in mucosal lymphoid organs. In conclusion, i.n. vaccination with gliadin, an environmental antigen with possible etiological influence in T1D, may represent a novel, safer strategy for prevention or even early cure of T1D.

• MeSH
• aplikace intranazální MeSH
• CD4-pozitivní T-lymfocyty imunologie   MeSH
• cytokiny metabolismus   MeSH
• diabetes mellitus 1. typu farmakoterapie   imunologie   prevence a kontrola   MeSH
• forkhead transkripční faktory metabolismus   MeSH
• gliadin aplikace a dávkování   terapeutické užití   MeSH
• gluteny aplikace a dávkování   MeSH
• lidé MeSH
• lymfoidní tkáň imunologie   patologie   MeSH
• myši inbrední NOD MeSH
• počet lymfocytů MeSH
• slizniční imunita MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• cytokiny MeSH
• forkhead transkripční faktory MeSH
• FOXP3 protein, human MeSH Prohlížeč
• gliadin MeSH
• gluteny MeSH

BACKGROUND: Environmental factors such as nutrition or exposure to infections play a substantial role in the pathogenesis of type 1 diabetes (T1D). We have previously shown that gluten-free, non-purified diet largely prevented diabetes in non-obese diabetic (NOD) mice. In this study we tested hypothesis that early introduction of gluten-enriched (gluten+) diet may increase diabetes incidence in NOD mice. METHODS: Standard, gluten-free, gluten+ modified Altromin diets and hydrolysed-casein-based Pregestimil diet were fed to NOD females and diabetes incidence was followed for 310 days. Insulitis score and numbers of gut mucosal lymphocytes were determined in non-diabetic animals. RESULTS: A significantly lower diabetes incidence (p < 0.0001) was observed in NOD mice fed gluten-free diet (5.9%, n = 34) and Pregestimil diet (10%, n = 30) compared to mice on the standard Altromin diet (60.6%, n = 33). Surprisingly, gluten+ diet also prevented diabetes incidence, even at the level found with the gluten-free diet (p < 0.0001, 5.9%, n = 34). The minority of mice, which developed diabetes on all the three diabetes-protective (gluten+, gluten-free, Pregestimil) diets, did that slightly later compared to those on the standard diet. Lower insulitis score compared to control mice was found in non-diabetic NOD mice on the gluten-free, and to a lesser extent also gluten+ and Pregestimil diets. No substantial differences in the number of CD3(+), TCR-gammadelta(+), and IgA(+) cells in the small intestine were documented. CONCLUSIONS: Gluten+ diet prevents diabetes in NOD mice at the level found with the non-purified gluten-free diet. Possible mechanisms of the enigmatic, dual effect of dietary gluten on the development of T1D are discussed.

• MeSH
• antigeny CD3 analýza   MeSH
• diabetes mellitus 1. typu imunologie   patologie   prevence a kontrola   MeSH
• dieta * MeSH
• genetická predispozice k nemoci MeSH
• gluteny aplikace a dávkování   MeSH
• ileum imunologie   MeSH
• imunoglobulin A metabolismus   MeSH
• imunoglobulin M metabolismus   MeSH
• jejunum imunologie   MeSH
• Langerhansovy ostrůvky patologie   MeSH
• myši inbrední NOD MeSH
• myši MeSH
• receptory antigenů T-buněk gama-delta analýza   MeSH
• zvířata MeSH
• Check Tag
• mužské pohlaví MeSH
• myši MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• antigeny CD3 MeSH
• gluteny MeSH
• imunoglobulin A MeSH
• imunoglobulin M MeSH
• receptory antigenů T-buněk gama-delta MeSH