Type 1 Diabetes (T1D) in humans and the non-obese diabetic (NOD) mouse model results from autoreactive T cell destruction of pancreatic beta cells. A pathogenic role for B lymphocytes (B cells) in T1D first became evident when NOD mice made deficient in this population through introduction of an inactivated Ig heavy chain gene (NOD.Ignull) or chronic treatment with anti-IgM antibodies were strongly protected from disease. We produced an NOD background strain developing a greatly decreased T1D incidence due to a NOR-derived 44.31Mb congenic region from rs3674285 to D4Mit127 on distal Chr. 4 (termed NOD.NOR-Chr4 (NR4)) containing disease resistance alleles decreasing the pathogenic activity of autoreactive B cells. Microarrays were conducted on B cells purified from spleens of NOD and NR4 mice to highlight differentially expressed genes within the distal Chr. 4 locus. B cells were either cultured in media alone (unstimulated) or with BCR cross-linking anti-IgM-F(ab)2 fragments (stimulated) for 2h before RNA was extracted for transcript analysis.
Subcongenic analyses reveal complex interactions between distal chromosome 4 genes controlling diabetogenic B cells and CD4 T cells in nonobese diabetic mice.
Sex, Age, Specimen part
View SamplesB7x (B7-H4 or B7S1) is the seventh member of the B7 family and the in vivo function remains largely unknown. Despite new genetic data linking the B7x gene with autoimmune diseases, how exactly it contributes to peripheral tolerance and autoimmunity is unclear. Here we showed that B7x protein was not detected on antigen-presenting cells or T cells in both human and mice, which is unique in the B7 family. As B7x protein is expressed in some peripheral cells such as pancreatic b cells, we utilized a CD8 T cell-mediated diabetes model (AI4ab) in which CD8 T cells recognize an endogenous self-antigen, and found that mice lacking B7x developed more severe diabetes than control AI4ab mice. Conversely, mice overexpressing B7x in the b cells (Rip-B7xAI4ab) were diabetes free. Furthermore, adoptive transfer of effector AI4ab CD8 T cells induced diabetes in control mice, but not in Rip-B7xAI4ab mice. Mechanistic studies revealed that pathogenic effector CD8 T cells were capable of migrating to the pancreas but failed to robustly destroy tissue when encountering local B7x in Rip-B7xAI4ab mice. Although AI4ab CD8 T cells in Rip-B7xAI4ab mice and AI4ab mice showed similar cytotoxic function, cell death, and global gene expression profiles, these cells had greater proliferation in AI4ab mice than in RIP-B7xAI4ab mice. These results suggest that B7x in nonlymphoid organs prevents peripheral autoimmunity partially through inhibiting proliferation of tissue-specific CD8 T cells and that local overexpression of B7x on pancreatic b cells is sufficient to abolish CD8 T cell-induced diabetes.
B7x in the periphery abrogates pancreas-specific damage mediated by self-reactive CD8 T cells.
Specimen part, Disease
View SamplesWe describe a function of focal adhesion kinase (FAK) in driving anti-tumor immune evasion. The kinase activity of nuclear-targeted FAK in squamous cancer cells drives exhaustion of CD8+ T-cells and recruitment of regulatory T-cells by transcriptionally regulating chemokine/cytokine and ligand-receptor networks, including transcription of Ccl5 that is crucial. These changes inhibit antigen-primed cytotoxic CD8+ T-cell activity, permitting growth of FAK-expressing tumors.
Nuclear FAK controls chemokine transcription, Tregs, and evasion of anti-tumor immunity.
Specimen part
View SamplesAutoantibodies that arise in autoimmunity can be present years to decades prior to the onset of disease manifestations. This suggests that the initial autoimmune trigger involves a peripheral lymphoid component, which then drives disease pathology in local tissues later in life. To explore the impact of early peripheral immune dysregulation on the progression of Sjgrens Syndrome, we blocked the CD40-CD40L pathway in young female NOD.H-2h4 mice at 4 weeks of age with a single injection of anti-CD40L antibody, and collected total salivary gland at the age of week 8, 16 and 24. RNA was extracted and submitted to transcriptome profiling using Affymetrix microarray.
Autoimmune manifestations in aged mice arise from early-life immune dysregulation.
Treatment
View SamplesTacrolimus and Sirolimus are commonly used to maintain immunosuppression in kidney transplantation. However, their effects on immune cells and allograft molecular profiles have not been elucidated.
Cellular and molecular immune profiles in renal transplant recipients after conversion from tacrolimus to sirolimus.
Specimen part, Treatment
View SamplesWe wanted to understand the consequences of GSK126-mediated Ezh2 inhibition in an orthotopic model of Kras-driven non-small cell lung cancer (NSCLC). We injected the NSCLC cells with above-mentioned genotype into Nude mice and treated them with GSK126 50mg/kg (daily) or vehicle. As additional control for Ezh2 specificity we treated one tumor with doxycycline that induces shRNA-mediated Ezh2 protein downregulation in those cells. Purified tumour cells were obtained by dissection and FACS sorting based of GFP expression. This experiment contributes the genome-wide response of NSCLC cells to Ezh2 inhibition in vivo. Overall design: We generated mRNA profiles of tumor cells tail vein injected into the lungs of Nude mice by deep sequencing. After FACS purification, RNA extraction and Bioanalyzer analysis, we processed only samples with high quality cellular and RNA profiles. Overall, we compared 10-day GSK126 treated cells (n=4) and up to 30 days GSK126 treated cells (n=3) to Captisol-treated samples (vehicle, n=2), using Illumina Hiseq2000. FACS sorted cells from individual animals were obtained by GFP expression. For H3K27ac and H2AK5ac profiling, we used KP primary tumors generated by injection of NSCLC into the tail vein of nude mice. Mice were sacrificed on the onset of shortness of breath and tissues were resuspended in ChIP lysis buffer.
Ezh2 inhibition in Kras-driven lung cancer amplifies inflammation and associated vulnerabilities.
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View SamplesLactoferrin is a highly multifunctional protein. Indeed, it is involved in many physiological functions, including regulation of iron absorption and immune responses.
A nutritional supplement containing lactoferrin stimulates the immune system, extends lifespan, and reduces amyloid <i>β</i> peptide toxicity in <i>Caenorhabditis elegans</i>.
No sample metadata fields
View SamplesNote: non-normalized values and associated raw data cannot be located by the submitter
Maternal nutrition induces pervasive gene expression changes but no detectable DNA methylation differences in the liver of adult offspring.
Sex, Specimen part
View SamplesThe aim of this study is to characterize transcriptional changes induced by maternal diet in several adult tissues and to test whether differences in DNA methylation or microRNA expression could explain these changes.
Maternal nutrition induces pervasive gene expression changes but no detectable DNA methylation differences in the liver of adult offspring.
Sex, Specimen part
View SamplesThe aim of this study is to characterize transcriptional changes induced by maternal diet in several adult tissues and to test whether differences in DNA methylation or microRNA expression could explain these changes.
Maternal nutrition induces pervasive gene expression changes but no detectable DNA methylation differences in the liver of adult offspring.
Sex, Specimen part
View Samples