Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Coeliac disease is a common enteropathy with a strong inherited risk characterised by dietary wheat, rye and barley induced T-cell activation. Although there is replicated linkage to 2q33, results are inconsistent from association studies of the most promising candidate genes: the CD28/CTLA4/ICOS cluster. CTLA4 plays a key role in regulating T lymphocyte mediated inflammatory responses, and variants in the 3' region influence development of diabetes and thyroid disease. We genotyped CTLA4 variants (-1722 C/T, -658 T/C, -318 C/T, +49 A/G, +1822 C/T, CT60 A/G) to tag all common haplotypes (>5% frequency) and an ICOS variant (IVS+173 C/T) in 340 white UK Caucasian coeliac disease cases. Strict ascertainment criteria for coeliac cases required both villous atrophy at diagnosis and positive serology. In total, 973 healthy controls were available for SNP, and 705 for CTLA4 haplotype, based association analyses. Coeliac disease showed weak association with the CTLA4 +1822T (P=0.019) and CT60 G (P=0.047) alleles. Strong association was seen with a common CTLA4 haplotype (P=0.00067, odds ratio 1.41) of frequency 32.7% in coeliac disease and 25.5% in healthy controls. A common CTLA4 haplotype shows strong association with coeliac disease, and contains multiple alleles reported to affect immunological function. Loss of tolerance to dietary antigens in coeliac disease may be mediated in part by heritable variants in co-signalling genes regulating T-cell responses.
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PMID:A common CTLA4 haplotype associated with coeliac disease. 1565 18

Idd9.3, a locus that determines susceptibility to the autoimmune disease type 1 diabetes (T1D) in the nonobese diabetic (NOD) mouse, has been mapped to the distal region of chromosome 4. In the current report we reduce the size of the Idd9.3 interval to 1.2Mb containing 15 genes, including one encoding the immune signaling molecule, 4-1BB, which shows amino acid variation between diabetes sensitive and resistant strains. 4-1BB, a member of the TNF receptor superfamily expressed by a variety of immune cells, mediates growth and survival signals for T cells. Functional analyses demonstrate that purified T cells from NOD congenic mice with the C57BL/10 (B10) allele at Idd9.3 produce more IL-2 and proliferate more vigorously in response to anti-CD3 plus immobilized 4-1BB ligand than T cells from NOD mice with the NOD allele at Idd9.3. In contrast, the response to anti-CD3 plus anti-CD28 costimulation was indistinguishable between the congenic strains, pinpointing the differences in NOD versus NOD.B10 Idd9.3 T cell responses to the 4-1BB costimulatory pathway. These data provide evidence in support of Idd9.3 as the locus encoding 4-1BB and suggest that the 4-1BB signaling pathway could have a primary function in the etiology of autoimmune disease.
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PMID:Genetic and functional association of the immune signaling molecule 4-1BB (CD137/TNFRSF9) with type 1 diabetes. 1599 81

Mice deficient in programmed cell death 1 (PD-1, Pdcd1), an immunoinhibitory receptor belonging to the CD28/cytotoxic T lymphocyte-associated antigen-4 family, spontaneously develop lupus-like autoimmune disease and autoimmune dilated cardiomyopathy on C57BL/6 and BALB/c backgrounds, respectively. However, how PD-1 deficiency induces different forms of autoimmune diseases on these two strains was unknown. Here, we report that PD-1 deficiency specifically accelerates the onset and frequency of type I diabetes in NOD (nonobese diabetic) mice, with strong T helper 1 polarization of T cells infiltrating into islets. These results suggest that PD-1 deficiency accelerates autoimmune predisposition of the background strain, leading to the induction of different forms of autoimmune diseases depending on the genetic background of the strain. Using NOD-Pdcd1-/- mice as an efficient animal model of type I diabetes, we screened diabetes-susceptible loci by genetic linkage analysis. The diabetic incidence of NOD-Pdcd1-/- mice was controlled by five genetic loci, including three known recessive loci [Idd (insulin-dependent diabetes) 1, Idd17, and Idd20] and two previously unidentified dominant loci [Iddp (Idd under PD-1 deficiency) 1 and Iddp2].
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PMID:Establishment of NOD-Pdcd1-/- mice as an efficient animal model of type I diabetes. 1608 65

Type 1 diabetes (T1D), a T-cell-mediated autoimmune disease, could be attributed to many defects in nonobese diabetic (NOD) mice, including deficient expressions of costimulatory molecules that impair antigen presentation. Thus, this deficient antigen presentation may result in a reduced ability to induce a tolerogenic response through negative selection/regulation of autoreactive T cells. Improperly activated T cells seem to be able to induce autoimmune responses causing diabetes. To re-establish tolerance to autoantigens by modulating costimulation, we constructed and tested a new type of DNA vaccine encoding a membrane-bound preproinsulin (mbPPI) and a chimeric gene vector encoding mutant B7.1/CD40L (mB7.1/CD40L) fusion protein. This mutant B7.1 binds CTLA4 but not CD28. We report that young NOD mice immunized with mbPPI along with mB7.1/CD40L DNA vectors significantly reduced diabetes incidence while treatment with CTLA4/IgG1 exacerbated diabetes. In conclusion, the combination of mbPPI and mB7.1/CD40L was able to protect against autoimmunity and diabetes in NOD mice possibly by promoting a more efficient presentation of autoantigen PPI and inducing specific tolerance to PPI by negatively regulating autoreactive T cells.
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PMID:DNA vaccination with an insulin construct and a chimeric protein binding to both CTLA4 and CD40 ameliorates type 1 diabetes in NOD mice. 1610 64

CD4+CD25+Foxp3+ regulatory T cells (T(reg)) are critical for controlling autoimmunity. Evidence suggests that T(reg) development, peripheral maintenance, and suppressive function are dependent on Ag specificity. However, there is little direct evidence that the T(reg) responsible for controlling autoimmunity in NOD mice or other natural settings are Ag specific. In fact, some investigators have argued that polyclonal Ag-nonspecific T(reg) are efficient regulators of immunity. Thus, the goal of this study was to identify, expand, and characterize islet Ag-specific T(reg) in NOD mice. Ag-specific T(reg) from NOD mice were efficiently expanded in vitro using IL-2 and beads coated with recombinant islet peptide mimic-MHC class II and anti-CD28 mAb. The expanded Ag-specific T(reg) expressed prototypic surface markers and cytokines. Although activated in an Ag-specific fashion, the expanded T(reg) were capable of bystander suppression both in vitro and in vivo. Importantly, the islet peptide mimic-specific T(reg) were more efficient than polyclonal T(reg) in suppressing autoimmune diabetes. These results provide a direct demonstration of the presence of autoantigen-specific T(reg) in the natural setting that can be applied as therapeutics for organ-specific autoimmunity.
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PMID:Expansion of functional endogenous antigen-specific CD4+CD25+ regulatory T cells from nonobese diabetic mice. 1611 93

Costimulatory signals regulate T-cell activation. To investigate the role of costimulation in autoimmunity and transplantation, we studied the BB rat model of type 1 diabetes. Diabetes-prone BB (BBDP) rats spontaneously develop disease when 55-120 days of age. We observed that two anti-CD28 monoclonal antibodies (mAb) with different functional activities completely prevented diabetes in BBDP rats. Anti-CD154 mAb delayed diabetes, whereas treatment with CTLA4-Ig or anti-CD80 mAb accelerated disease. Anti-CD86 or anti-CD134L mAbs had no effect. Diabetes resistant BB (BBDR) rats are disease-free, but >95% of them develop diabetes after treatment with polyinosinic-polycytidylic acid and an mAb that depletes Treg cells. In the induced BBDR model, anti-CD154 mAb delayed onset of diabetes, whereas CTLA4-Ig, anti-CD134L or either of the anti-CD28 mAbs had little or no effect. In contrast, blockade of the CD134-CD134L pathway was highly effective for preventing autoimmune recurrence against syngeneic islet grafts in diabetic BBDR hosts. Blockade of the CD40-CD154 pathway was also effective, but less so. These data suggest that the effectiveness of costimulation blockade in the treatment of type 1 diabetes is dependent on both the costimulatory pathway targeted and the mechanism of induction, stage, intensity and duration of the pathogenic process.
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PMID:Costimulation and autoimmune diabetes in BB rats. 1661 20

Asthma and type I diabetes are major causes of chronic illness in childhood which, according to the current paradigm, have mutually antagonistic immunopathologies. Nonetheless, the disorders appear to preferably coexist both on population and individual levels. To assess whether children with asthma and type I diabetes might have a common immunoregulatory defect. The spontaneous and anti-CD3+ anti-CD28-stimulated cytokine production patterns by peripheral blood mononuclear cells of 13 children with both asthma and diabetes, nine children with diabetes, 11 children with asthma and nine healthy children were assessed using cytometric bead assay. The spontaneous production of IFN-gamma, TNF-alpha and IL-10 by mononuclear cells in children with both asthma and diabetes was elevated compared to the other study groups (p=0.02, p=0.001 and p=0.04, respectively). Stimulation in vitro increased IL-10 secretion in solely diabetic (p=0.008), asthmatic (p=0.008) and healthy children (p=0.01), but not in children with both diseases (p=0.22). Children suffering from both diabetes and asthma display a unique cytokine secretion pattern, distinct from those of solely diabetic, asthmatic and healthy children. In particular, these children appear to have a defect in regulation of IL-10 secretion.
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PMID:Unique cytokine secretion profile in children with both type I diabetes and asthma distinct from that of solely diabetic or asthmatic children. 1677 30

DNA vaccination of autoimmune diabetes-prone NOD mice with unmodified target islet antigens, i.e., preproinsulin (PPIns) or glutamic acid decarboxylase 65 (GAD65), is poorly protective. However, in this study, we demonstrate protection against disease by covaccination with a mutant B7-1 molecule (B7-1wa) that binds the negative T cell regulator CTLA-4 (CD152), but not CD28. Codelivery of plasmids encoding a PPIns-GAD65 fusion construct and B7-1wa protected against both insulitis and diabetes. In vitro, the T cells of covaccinated mice had negative responses to both insulin and GAD65, and this was restored by adding blocking antibodies to transforming growth factor beta1 (TGF-beta1), suggesting a role for this cytokine. Adoptive transfer experiments revealed that DNA vaccination generated protective CD4(+) regulatory T cells (Tr) of either CD25(+) or CD25(-) phenotype. Furthermore, vaccinated mice had increased numbers of T cells with Tr-associated markers, such as CTLA-4, Foxp3, and membrane-bound TGF-beta1. Tr cells inhibited the responses of diabetogenic T cells to islet antigens, and depletion of T cells expressing membrane-bound TGF-beta1 abolished the suppressive effect. Thus, selective engagement of CTLA-4 during islet-antigen DNA vaccination induces Tr cells that protect against this autoimmune disease.
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PMID:Protective regulatory T cell generation in autoimmune diabetes by DNA covaccination with islet antigens and a selective CTLA-4 ligand. 1679 Mar 65

CTL-associated antigen 4 (CTLA-4) engagement negatively regulates T cell activation and function and promotes immune tolerance. However, it has been difficult to explore the biology of selective engagement of CTLA-4 in vivo because CTLA-4 shares its ligands, B7-1 and B7-2, with CD28. To address this issue, we developed a Tg mouse expressing a single-chain, membrane-bound anti-CTLA-4 Ab (scFv) on B cells. B and T cells developed normally and exhibited normal phenotype in the steady state and after activation in these mice. However, B cells from scFv Tg+ mice (scalphaCTLA4+) prevented T cell proliferation and cytokine production in mixed lymphocyte reactions. Additionally, mice treated with scalphaCTLA4+ B cells had decreased T cell-dependent B cell Ab production and class switching in vivo after antigen challenge. Furthermore, expression of this CTLA-4 agonist protected NOD mice from spontaneous autoimmune diabetes. Finally, this disease prevention occurred in Treg-deficient NOD.B7-1/B7-2 double-knockout mice, suggesting that the effect of the CTLA-4 agonist directly attenuates autoreactive T cell activation, not Treg activation. Together, results from this study demonstrate that selective ligation of CTLA-4 attenuates in vivo T cell responses, prevents development of autoimmunity, and represents a novel immunotherapeutic approach for the induction and maintenance of peripheral tolerance.
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PMID:Inhibition of T cell activation and autoimmune diabetes using a B cell surface-linked CTLA-4 agonist. 1688 54

Constitutive presentation of tissue Ags by dendritic cells results in tolerance of autoreactive CD8+ T cells; however, the underlying molecular mechanisms are not well understood. In this study we show that programmed death (PD)-1, an inhibitory receptor of the CD28 family, is required for tolerance induction of autoreactive CD8+ T cells. An antagonistic Ab against PD-1 provoked destructive autoimmune diabetes in RIP-mOVA mice expressing chicken OVA in the pancreatic islet cells, which received naive OVA-specific CD8+ OT-I cells. This effect was mediated by the PD ligand (PD-L) PD-L1 but not by PD-L2. An increased number of effector OT-I cells recovered from the pancreatic lymph nodes of anti-PD-L1-treated mice showed down-regulation of PD-1. Furthermore, the blockade of PD-1/PD-L1 interaction during the priming phase did not significantly affect OT-I cell division but enhanced its granzyme B, IFN-gamma, and IL-2 production. Thus, during the presentation of tissue Ags to CD8+ T cells, PD-1/PD-L1 interaction crucially controls the effector differentiation of autoreactive T cells to maintain self-tolerance.
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PMID:Cutting Edge: Programmed death (PD) ligand-1/PD-1 interaction is required for CD8+ T cell tolerance to tissue antigens. 1714 23


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