Rapamycin-Gliadin Composite Nanoparticles Enhance Hepato-Splenic Dialogue for Gluten Tolerance in Celiac Disease
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PROVIDER: PRJNA1149773 | ENA |
REPOSITORIES: ENA
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Project description:Background Celiac disease (CeD) is an autoimmune disorder triggered by gluten, with gliadin as the primary antigen. Therapies targeting gliadin to induce antigen-specific immune tolerance are of significant interest. This study investigates the therapeutic potential of a novel rapamycin-gliadin composite nanoparticle (PLN-GR) in enhancing Kupffer cell-mediated hepato-splenic dialogue to promote gluten tolerance in CeD. Methods Rapamycin-gliadin composite nanoparticles were synthesized using a precipitation self-assembly method and characterized for size, zeta potential, and cellular uptake. A CeD delayed-type hypersensitivity (DTH) mouse model was employed to evaluate the immunomodulatory effects of PLN-GR. Cellular biodistribution, immune phenotyping, and metabolic assessments were conducted to elucidate the nanoparticles' mechanism of action. Results Rapamycin-gliadin composite nanoparticles effectively targeted the liver and were internalized by Kupffer cells, inducing a tolerogenic phenotype. In vivo treatment with PLN-GR ameliorated systemic and intestinal inflammation in the CeD DTH mouse model, evidenced by reduced paw swelling and intestinal histopathology. The nanoparticles induced a metabolic shift from glycolysis to oxidative phosphorylation in macrophages, associated with increased itaconate production. This metabolic reprogramming was linked to an increase in PD-L1+ tolerogenic dendritic cells and a decrease in Th1 cell counts in the spleen. Conclusion The study demonstrates that rapamycin-gliadin nanoparticles can induce antigen-specific tolerance in CeD by modulating hepatic and splenic immune responses. The findings suggest a potential therapeutic strategy for CeD by enhancing immunometabolic reprogramming and inter-organ communication.
2025-07-30 | GSE275197 | GEO
Project description:Study on the effects of long term, dietary, consumption of gliadin (gluten) in patients with celiac disease. Comparison of expression profiles of biopsies from normalized patients treated with gluten-free diet >2 years (FU-follow-up samples) versus biopsies from patients with active disease (Dx-at diagnosis samples)
2009-06-01 | E-MEXP-1828 | biostudies-arrayexpress
Project description:Study of the effects of re-exposure to gliadin of intestinal biopsies from normalized celiac patients (>2 years on gluten free diet). Comparison of the expresson profile in biopsy portions incubated with 10ug/ml gliadin versus without gliadin for 4 hours.
2009-06-01 | E-MEXP-1823 | biostudies-arrayexpress
Project description:Analysis of the influence of celiac disease-associated bacteria and gluten on intestinal epithelial cells
2017-09-01 | GSE103374 | GEO
Project description:Dietary gluten proteins (prolamins) from wheat, rye, and barley are the driving forces behind celiac disease, an organ-specific autoimmune disorder that targets both the small intestine and organs outside the gut. In the small intestine, gluten induces inflammation and a typical morphological change of villous atrophy and crypt hyperplasia. Gut lesions improve and heal when gluten is excluded from the diet and the disease relapses when patients consume gluten. Oral immune tolerance towards gluten may be kept for years or decades before breaking tolerance in genetically susceptible individuals. Celiac disease provides a unique opportunity to study autoimmunity and the transition in immune cells as gluten breaks oral tolerance. Seventy-three celiac disease patients on a long-term gluten-free diet ingested a known amount of gluten daily for six weeks. A peripheral blood sample and intestinal biopsies were taken before and six weeks after initiating the gluten challenge. Biopsy results were reported on a continuous numeric scale that measured the villus height to crypt depth ratio to quantify gluten-induced gut mucosal injury. Pooled B and T cells were isolated from whole blood, and RNA was analyzed by DNA microarray looking for changes in peripheral B- and T-cell gene expression that correlated with changes in villus height to crypt depth, as patients maintained or broke oral tolerance in the face of a gluten challenge.
2017-01-27 | GSE87629 | GEO
Project description:Analysis of the influence of celiac disease-associated bacteria and gluten on intestinal epithelial cells
2017-08-26 | GSE103100 | GEO
Project description:Gluten-containing grains cause adverse health effects in individuals with celiac disease. Fermentation of these grains results in gluten-derived polypeptides with largely uncharacterized sizes and sequences, which may still trigger an immune response. This research used N-terminal labeling mass spectrometry to characterize protein hydrolysates during each stage of bench-scale brewing, including malting, mashing, boiling, fermentation, and aging. Gluten hydrolysates from each brewing step were tracked and the immunotoxic potential was evaluated in silico. The results indicate that proteolysis and precipitation of gliadins occurring during brewing differ by protein region and brewing stage. The termini of gliadins were hydrolyzed throughout the entire brewing process, but the central regions remained relatively stable. Most hydrolysis occurred during malting, and most precipitation occurred during boiling. The addition of yeast yielded new cleavage sites but did not result in complete hydrolysis. Consistent detection of peptides within the clinically important regions of gliadin corroborated the hydrolytic resistance of this region. N-terminal labeling mass spectrometry served as a novel approach to track the fate of gliadin/gluten throughout bench-scale brewing. Consistently identified fragments could serve as improved targets for detection of hydrolyzed gluten in fermented products.
2021-07-23 | PXD023482 | Pride
Project description:Background & Aims: Traditional celiac disease diagnostics based on histomorphometric evaluations are liable to misinterpretations due to the common technical flaws e.g. wrong orientation of the biopsy and subjective errors are relatively common e.g. interobserver errors. We envisioned that there is a need for molecular histomorphometric tool that obviates these error sources yielding an objective ratio instead. Gene expression determine the state of a tissue, so the changes in expression may be associated with the severity of lesions during CD and can be used to classify it. Methods: 15 CD patients, who have been at least one year on gluten-free diet, were enrolled. All participants were biopsied before and after the gluten challenge (10 weeks, 4 grams of gluten daily). 6 healthy non-CD individuals were included as controls. Biopsies were taken on PAXgene biological fixative and embedded in paraffin and Vh/Cd ratio was assessed. RNA was extracted from the same sections and subjected to genome-wide 3’RNA-sequencing. Sequencing data was used to determine differentially expressed genes and regression model, that successfully describes the mucosal damage, was created and tested in independent material. Results: 167 differentially expressed genes were identified in healthy vs. treated CD comparisons with 117 genes downregulated and 50 genes upregulated. 415 differentially expressed genes were identified in Post gluten challenge to Treated CD comparisons with 195 genes downregulated and 220 genes upregulated. 119 genes whose expression highly correlates to Vh/Cd ratio (Spearman’s rank correlation coefficient, |rho|>0.7) were identified. Gene ontology analyses show that genes involved in cellular response to cytokines, including interferons, were over-represented. Stepwise regression allowed us computationally cut down the number of genes, that describe Vh/Cd ratio changes, to 7 and IELs number to 5. Created models describe 98.9% of observed Vh/Cd and 97.5% of IELs number variabilities; there is a strong correlation between the model’s predicted and observed ratios. Conclusions: Adoption of molecular histomorphometry, with our selected set of target genes, is quantitative and reliable way of estimating gluten-induced mucosal injury and inflammation. By including this technology one can overcome the typical shortcomings common in celiac disease diagnostics based on traditional histomorphometry analyses alone. Likewise, molecular histomorphometry is a promising instrument when incorporated in clinical trials where assessing drug efficacy on mucosal health is paramount. In addition, despite deemed healthy, based on traditional histomorphometric analyses, celiac patients on gluten free diet have significantly distinctive molecular histomorphometric pattern when compared to healthy controls.
2020-07-21 | GSE145358 | GEO
Project description:Celiac disease (CeD) is an intestinal immune-mediated disorder caused by gluten ingestion in genetically predisposed subjects. CeD is characterized by villous atrophy, altered intestinal permeability, crypt hyperplasia and innate and adaptive immune response. This study aimed to develop and validate the use of intestinal organoids from celiac patients to study CeD. A repository of organoids from duodenum of non-celiac and celiac patients was generated and characterized accordingly to standard procedures. RNA-seq analysis was employed to study the global gene expression program of CeD (n=3) and non-CeD (n=3) organoids sets. While the three celiac derived organoids shared similar transcriptional signatures the NC samples set appeared more heterogeneous. We found 486 genes differentially expressed between the two groups. Of them, 299 genes were downregulated (FC<2; FDR<0.05) and 187 were upregulated in CeD (FC >2; FDR<0.05). We observed CeD organoids had significantly altered expression of genes associated with barrier function, innate immunity, and stem cell function.
2019-05-29 | GSE113492 | GEO
Project description:Celiac disease (CD) is an autoimmune disease in which intestinal inflammation is induced by dietary gluten. The means through which gluten-specific CD4+T cell activation culminates in intraepithelial T cell (T-IEL)–mediated intestinal damage remain unclear. Here, we performed multiplexed single-cell analysis of intestinal and gluten-induced peripheral blood T cells from patients in different CD states and healthy controls. Untreated, active, and potential CD were associated with an enrichment of activated intestinal T cell populations, including CD4+follicular T helper (TFH) cells, regulatory T cells (Tregs), and natural CD8+αβ and γδ T-IELs. Natural CD8+αβ and γδ T-IELs expressing activating natural killer cell receptors (NKRs) exhibited a distinct TCR repertoire in CD and persisted in patients on a gluten-free diet without intestinal inflammation. Our data further show that NKR-expressing cytotoxic cells, which appear to mediate intestinal damage in CD, arise from a distinct NKR-expressing memory population of T-IELs. After gluten ingestion, both αβ and γδ T cell clones from this memory population of T-IELs circulated systemically along with gluten-specific CD4+T cells and assumed a cytotoxic and activating NKR-expressing phenotype. Collectively, these findings suggest that cytotoxic T cells in CD are rapidly mobilized in parallel with gluten-specific CD4+T cells after gluten ingestion.
2024-01-13 | GSE252762 | GEO