Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0011854 (type 1 diabetes)
 20,749 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Autoantigen-specific immunotherapy promises effective treatment for devastating tissue specific autoimmune diseases like multiple sclerosis (MS) and type 1 diabetes (T1D). Because activated dendritic cells (DCs) stimulate the differentiation of autoreactive T cells involved in the initiation of autoimmunity, blocking the activation of DCs may be an effective strategy for inhibiting tissue specific autoimmunity. Following this approach, immature DCs were shown to remain inactive after treatment with chimeric fusion proteins composed of the cholera toxin B subunit adjuvant linked to autoantigens like proinsulin (CTB-INS). Mass spectrometer analysis of human DCs treated with CTB-INS suggest that upregulation of the tryptophan catabolic enzyme indoleamine 2, 3-dioxygenase (IDO1) is responsible for inhibiting DC activation thereby resulting in a state of immunological tolerance within the DC. Here we show that the fusion protein CTB-INS inhibits human monocyte derived DC (moDC) activation through stimulation of IDO1 biosynthesis and that the resultant state of DC tolerance can be further enhanced by the presence of residual E. coli lipopolysaccharide (LPS) present in partially purified CTB-INS preparations. Additional experiments showed that LPS enhancement of DC tolerance was dependent upon stimulation of IDO1 biosynthesis. LPS stimulation of increased levels of IDO1 in the DC resulted in increased secretion of kynurenines, tryptophan degradation products known to suppress DC mediated pro-inflammatory T cell differentiation and to stimulate the proliferation of regulatory T cells (Tregs). Further, the presence of LPS in CTB-INS treated DCs stimulated the biosynthesis of costimulatory factors CD80 and CD86 but failed to upregulate maturation factor CD83, suggesting CTB-INS treated DCs may be maintained in a state of semi-activation. While treatment of moDCs with increasing amounts of LPS free CTB-INS was shown to increase DC secretion of the anti-inflammatory cytokine IL-10, the presence of residual LPS in partially purified CTB-INS preparations dramatically increased IL-10 secretion, suggesting that CTB-INS may enhance DC mediated immunological tolerance by stimulating the proliferation of anti-inflammatory T cells. While the extraction of LPS from bacterial generated CTB-INS may remove additional unknown factors that may contribute to the regulation of IDO1 levels, together, our experimental data suggest that LPS stimulates the ability of CTB-INS to induce IDO1 and IL-10 important factors required for establishment of a state of functional immunological tolerance in human DCs. Regulation of the ratio of LPS to CTB-INS may prove to be an effective method for optimization of readily available "off the shelf" CTB-INS mediated immune-therapy for tissue specific autoimmune diseases including type 1 diabetes.
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PMID:LPS enhances CTB-INSULIN induction of IDO1 and IL-10 synthesis in human dendritic cells. 3091 Feb 18

Patients with diabetes develop endothelial dysfunction shortly after diabetes onset that progresses to vascular disease underlying the majority of diabetes-associated comorbidities. Increased lipid peroxidation, mitochondrial calcium overload, and mitochondrial dysfunction are characteristics of dysfunctional endothelial cells in diabetic patients. We here identified that targeting the lipid peroxidation product 12(S)-hydroxyeicosatetraenoic acid-induced [12(S)-HETE-induced] activation of the intracellularly located cation channel transient receptor potential vanilloid 1 (TRPV1) in endothelial cells is a means to causally control early-stage vascular disease in type I diabetic mice. Mice with an inducible, endothelium-specific 12/15-lipoxygenase (12/15Lo) knockout were protected similarly to TRPV1-knockout mice from type 1 diabetes-induced endothelial dysfunction and impaired vascular regeneration following arterial injury. Both 12(S)-HETE in concentrations found in diabetic patients and TRPV1 agonists triggered mitochondrial calcium influx and mitochondrial dysfunction in endothelial cells, and 12(S)-HETE effects were absent in endothelial cells from TRPV1-knockout mice. As a therapeutic consequence, we found that a peptide targeting 12(S)-HETE-induced TRPV1 interaction at the TRPV1 TRP box ameliorated diabetes-induced endothelial dysfunction and augmented vascular regeneration in diabetic mice. Our findings suggest that pharmacological targeting of increased endothelial lipid peroxidation can attenuate diabetes-induced comorbidities related to vascular disease.
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PMID:12(S)-HETE mediates diabetes-induced endothelial dysfunction by activating intracellular endothelial cell TRPV1. 3258 93

Neuropathic pain is a common complication of diabetes with high morbidity and poor treatment outcomes. Accumulating evidence suggests the immune system is involved in the development of diabetic neuropathy, whilst neuro-immune interactions involving the kynurenine (KYN) and tetrahydrobiopterin (BH4) pathways have been linked to neuropathic pain pre-clinically and in several chronic pain conditions. Here, using a multiplex assay, we quantified serum levels of 14 cytokines in 21 participants with type 1 diabetes mellitus, 13 of which were classified as having neuropathic pain. In addition, using high performance liquid chromatography and gas chromatography-mass spectrometry, all major KYN and BH4 pathway metabolites were quantified in serum from the same cohort. Our results show increases in GM-CSF and IL-8, suggesting immune cell involvement. We demonstrated increases in two inflammatory biomarkers: neopterin and the KYN/TRP ratio, a marker of indoleamine 2,3-dioxygenase activity. Moreover, the KYN/TRP ratio positively correlated with pain intensity. Total kynurenine aminotransferase activity was also higher in the diabetic neuropathic pain group, indicating there may be increased production of the KYN metabolite, xanthurenic acid. Overall, this study supports the idea that inflammatory activation of the KYN and BH4 pathways occurs due to elevated inflammatory cytokines, which might be involved in the pathogenesis of neuropathic pain in type 1 diabetes mellitus. Further studies should be carried out to investigate the role of KYN and BH4 pathways, which could strengthen the case for therapeutically targeting them in neuropathic pain conditions.
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PMID:Kynurenine, Tetrahydrobiopterin, and Cytokine Inflammatory Biomarkers in Individuals Affected by Diabetic Neuropathic Pain. 3297 38


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