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

Pancreases of untreated and nicotinamide (NIC)-treated pre-diabetic (10-week-old) and overtly diabetic (25-week-old) female NOD (non-obese diabetic) mice and of NON (non-obese non-diabetic) control mice were studied, with the following results. (1) Islets and ducts of overtly diabetic untreated NOD mice (25-week-old) were found to express low levels of MHC class I and II molecules, like NON controls, and high levels of adhesive molecules. (2) NIC was able to slightly affect glycaemia and insulitis, slowing down diabetes progression. Moreover it significantly decreased MHC class II expression (but not class I) in vivo by week 10, and significantly enhanced intercellular adhesion molecule-1 (ICAM-1) expression, mainly by week 25, within the pancreas, where 5-bromo-2'-deoxyuridine positive nuclei and insulin positive cells were present, demonstrating that a stimulation of endocrine cell proliferation occurs. (3) In addition, NIC partly counteracted the fall of superoxide dismutase levels, observed in untreated diabetic NOD animals. (4) In vitro studies demonstrated that NIC: (i) was able to significantly reduce nitrite accumulation and to increase NAD+NADH content significantly, and (ii) was able to increase the levels of interleukin-4, a T helper 2 lymphocyte (Th2) protective cytokine, and of interferon-alpha (IFN-alpha), which is known to be able to induce MHC class I and ICAM-1 but not MHC class II expression, as well as IFN-gamma, which is also known to be able to induce MHC class I and ICAM-1 expression. The latter, although known to be a proinflammatory Th1 cytokine, has also recently been found to exert an anti-diabetogenic role. This study therefore clearly shows that adhesive mechanisms are ongoing during the later periods of diabetes in pancreatic ducts of NOD mice, and suggests they may be involved in a persistence of the immune mechanisms of recognition, adhesion and cytolysis and/or endocrine regeneration or differentiation processes, as both NIC-increased ICAM-1 expression and 5-bromo-2'-deoxyuridine positivity imply. The effects of NIC on MHC class II (i.e. a reduction) but not class I, and, mainly, on ICAM-1 expression (i.e. an increase), together with the increase in Th2 protective cytokine levels are very interesting, and could help to explain its mechanism of action and the reasons for alternate success or failure in protecting against type 1 diabetes development.
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PMID:Nicotinamide decreases MHC class II but not MHC class I expression and increases intercellular adhesion molecule-1 structures in non-obese diabetic mouse pancreas. 1007 85

The NOD (nonobese diabetic) mouse is a good animal model for human IDDM. MHC class II-restricted CD4 T cells are necessary for the onset of diabetes in NOD mice. Here, we demonstrate that NOD mice lacking the CIITA (class II transactivator) molecule, and hence deficient in MHC class II expression and peripheral CD4 T cells, show significant pancreatic infiltration but do not develop diabetes. CD4 T cell deficiency, then, does not prevent initial pancreatic infiltration, but does stop progression to insulitis. Adoptive transfer studies show that the paucity of CD4 T cells in NOD-CIITA knockout mice is responsible for the absence of diabetes, since the CD8 T cell and B cell compartments are functional. An autoaggressive CD8+ T cell clone can, however, transfer diabetes in CIITA knockout recipient mice without CD4 T cell help, albeit with some delay compared with that in CIITA-sufficient recipients. This highlights the fact that a high number of in vitro activated autoaggressive CD8 T cells can over-ride the requirement for CD4 T cell help for the onset of diabetes.
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PMID:Pancreatic infiltration but not diabetes occurs in the relative absence of MHC class II-restricted CD4 T cells: studies using NOD/CIITA-deficient mice. 1020 97

Clinical trials that test the efficacy of Phlogenzym (consisting of the hydrolytic enzymes bromelain and trypsin and the anti-oxidant rutosid) as a treatment for T cell-mediated autoimmune diseases including multiple sclerosis (MS), type 1 diabetes and rheumatoid arthritis are presently ongoing. We tested the effects of Phlogenzym treatment in the murine model for MS, experimental allergic encephalomyelitis (EAE), a disease induced in SJL mice by immunization with proteolipid protein (PLP) peptide 139-151. Oral administration of Phlogenzym resulted in complete protection from EAE. In Phlogenzym-treated mice, the dose response curve of the PLP:139-151-specific T cell response was shifted to the right, that is, the primed T cells required higher peptide concentrations to become activated. Additionally, the T cell response to this peptide was shifted towards the T helper 2 cytokine profile. Both effects are consistent with an increased T cell activation threshold. In support of this interpretation, we found that the accessory molecules CD4, CD44, and B7-1 (all of which are involved in T cell co-stimulation) were cleaved by Phlogenzym, while CD3 and MHC class II molecules (which are involved in the recognition of antigens by T cells) and LFA-1 were unaffected. These data show the efficacy of oral Phlogenzym treatment in an animal model of T cell-mediated autoimmune disease and suggest that the protective effect might be the result of an increase in the activation threshold of the autoreactive T lymphocytes brought about by the cleavage of accessory molecules involved in the interaction of T cells and antigen presenting cells.
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PMID:Prevention of murine EAE by oral hydrolytic enzyme treatment. 1022 28

Type 1 diabetes is a major histocompatibility complex (MHC) class II-associated autoimmune disease mediated by beta-cell-specific T-cells and characterized by circulating autoantibodies to beta-cell molecules. In the BB/Wor diabetes-prone (DP) rat, type 1 diabetes develops spontaneously with an incidence of >90%. BB diabetes can be adoptively transferred to naive syngeneic or MHC class II-compatible rats with islet cell-activated T-cell lines derived from diabetic BB/Wor rats. However, the target beta-cell autoantigen(s) in BB diabetes has not yet been defined. BB rat T-cell lines activated in vitro with antigen-presenting cells (APC) and BB islet cell crude membranes (CM), but not islet cell cytosol, adoptively transfer diabetes into young DP recipients. To determine if the target autoantigen is an integral or peripheral membrane protein, islet cell CM were treated with 0.5 mol/l KCl or 0.2 mol/l Na2CO3 (pH 11). Both treatments selectively extract peripheral proteins from the cell membrane without affecting the disposition of integral (transmembrane) proteins. T-cell lines activated in vitro with APC and 0.5 mol/l KCl, or pH 11 (0.2 mol/l Na2CO3)-treated islet cell CM, transferred diabetes into young DP rats. Conversely, T-cell lines activated in vitro with APC and the supernatant of 0.5 mol/l KCl-treated CM (containing extracted peripheral proteins), did not adoptively transfer diabetes. After activation in vitro with islet cell membrane antigens, the diabetes-inducing cell lines were comprised of both CD4+ CD8- T-cells and 10-30% B-cells. We conclude that a major CD4+ T-cell target autoantigen in BB diabetes is a membrane-associated beta-cell molecule with the characteristics of an integral beta-cell membrane protein. The identification of this MHC class II-restricted beta-cell target molecule will allow the design of antigen-specific intervention protocols to prevent the onset of type 1 diabetes in genetically susceptible individuals.
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PMID:Islet cell membrane antigens activate diabetogenic CD4+ T-cells in the BB/Wor rat. 1033

The major histocompatibility complex (MHC) genes play a significant role in the predisposition to insulin-dependent diabetes mellitus or type 1 diabetes. HLA-DQ8 (DQB1*0302, DQA 1*0301) genes have been shown to have the highest relative risk for human type 1 diabetes. To develop a "humanized" mouse model of diabetes, HLA-DQ8 was transgenically expressed in mice lacking endogenous class II genes. Since non-MHC background genes of the NOD influence the disease process, AP"/DQ8 mice were mated with the NOD strain and backcrossed to generate Abeta degree/DQ8/NOD mice. These mice have DQ8 as the sole MHC class II restriction element with NOD background genes at the N 2 generation. The DQ8 transgenic mice were used to identify T cell epitopes on glutamic acid decarboxylase (GAD 65), an important putative autoantigen in type 1 diabetes. The NOD background genes strongly influenced antigen processing, that is, different T cell epitopes were generated from the processing of GAD 65 in vivo in the Abeta degree/DQ8 and in the Abeta degree/DQ8/NOD mice.
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PMID:NOD background genes influence T cell responses to GAD 65 in HLA-DQ8 transgenic mice. 1042 75

Type 1 Diabetes mellitus (IDDM) results from an immune-mediated destruction of the pancreatic b-cells. The genetic predisposition is mainly confered by variations within MHC class II region on chromosome 6p as well as the CTLA4 gene located on chromosome 2q33. We analysed the transmission of HLA DQA1, DQB1, DRB1*04 alleles as well as an endogenous retroviral element (DQLTR3) in 130 families with a type 1 diabetic offspring in order to evaluate their role in genetic susceptibility to IDDM. Also the combined transmission of HLA and CTLA4 haplotypes was investigated. MHC class II alleles were typed using sequence-specific primer analysis. The presence or absence of DQLTR3 was defined by a nested PCR approach and CTLA4 microsatellite polymorphisms were detected with fluorescence-labeled primer on an automated sequencing system. By transmission distortion test we confirm the linkage of HLA DQA1*0501 DQB1*0201 (DR3 DQ2) as well as DQA1*0301 DQB1*0302 (DR4 DQ8) with IDDM. Whereas the combination with CTLA4 risk markers leads to the highest transmission rate on DR3 positive haplotypes, the predisposing CTLA4 variant does not modulate the risk on DR4 haplotypes. However, the absence of DQLTR3 on DR3, but its presence on DR4 haplotypes significantly increases the genetic risk for type 1 diabetes. Therefore predisposing MHC class II haplotypes are defined by distinct loci which differentially control genetic susceptibility. The combined transmission of protective CTLA4 and HLA DR3 as well as DR4 haplotypes confirms the dominant role of HLA class II polymorphisms in defining disease susceptibility to type 1 diabetes mellitus.
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PMID:Genetic susceptibility to type 1 diabetes: clinical and molecular heterogeneity of IDDM1 and IDDM12 in a german population. 1052 14

The non-obese diabetic (NOD) mouse develops insulin dependent diabetes mellitus (IDDM) spontaneously with a higher incidence in females than in males. There are many similarities to the human disease, making it an ideal model. Our group is examining the role that CD4(+) and CD8(+) T cells play in IDDM in the NOD mouse, as it is known that both T cell subsets are required for onset of disease. Although IDDM has an autoimmune etiology, the initial triggering event is unknown and the autoantigen involved has not been identified. This investigation focussed on one of the potential autoantigens involved, the enzyme glutamic acid decarboxylase (GAD). We raised GAD peptide-specific CD8(+) T cells by immunising NOD mice with the GAD peptide alongside an irrelevant peptide that induced a CD4(+) T cell response. In order to maintain these peptide specific T cells in vitro and generate clones, it was found that antibodies specific to CD4(+) and MHC class II molecules needed to be included in the culture medium. This paper outlines the methods we employed to generate and maintain these CD8(+) T cells in vitro.
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PMID:Generation and maintenance of autoantigen-specific CD8(+) T cell clones isolated from NOD mice. 1055 46

Although DQA1*0301/DQB1*0302 is the human histocompatibility leukocyte antigen (HLA) class II gene most commonly associated with human type 1 diabetes, direct in vivo experimental evidence for its diabetogenic role is lacking. Therefore, we generated C57BL/6 transgenic mice that bear this molecule and do not express mouse major histocompatibility complex (MHC) class II molecules (DQ8(+)/mII(-)). They did not develop insulitis or spontaneous diabetes. However, when DQ8(+)/mII(-) mice were bred with C57BL/6 mice expressing costimulatory molecule B7-1 on beta cells (which normally do not develop diabetes), 81% of the DQ8(+)/mII(-)/B7-1(+) mice developed spontaneous diabetes. The diabetes was accompanied by severe insulitis composed of both T cells (CD4(+) and CD8(+)) and B cells. T cells from the diabetic mice secreted large amounts of interferon gamma, but not interleukin 4, in response to DQ8(+) islets and the putative islet autoantigens, insulin and glutamic acid decarboxylase (GAD). Diabetes could also be adoptively transferred to irradiated nondiabetic DQ8(+)/mII(-)/B7-1(+) mice. In striking contrast, none of the transgenic mice in which the diabetes protective allele (DQA1*0103/DQB1*0601, DQ6 for short) was substituted for mouse MHC class II molecules but remained for the expression of B7-1 on pancreatic beta cells (DQ6(+)/mII(-)/B7-1(+)) developed diabetes. Only 7% of DQ(-)/mII(-)/B7-1(+) mice developed diabetes at an older age, and none of the DQ(-)/mII(+)/B7-1(+) mice or DQ8(+)/mII(+)/B7-1(+) mice developed diabetes. In conclusion, substitution of HLA-DQA1*0301/DQB1*0302, but not HLA-DQA1*0103/DQB1*0601, for murine MHC class II provokes autoimmune diabetes in non-diabetes-prone rat insulin promoter (RIP).B7-1 C57BL/6 mice. Our data provide direct in vivo evidence for the diabetogenic effect of this human MHC class II molecule and a unique "humanized" animal model of spontaneous diabetes.
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PMID:In vivo evidence for the contribution of human histocompatibility leukocyte antigen (HLA)-DQ molecules to the development of diabetes. 1062 Jun 8

The murine MHC class II variant I-Ad confers susceptibility to herpes simplex virus (HSV)-induced keratitis and relative protection against type 1 diabetes mellitus. The association to these autoimmune diseases appears to be largely determined by the peptide sidechain specificity of the P9 pocket, which we therefore have analyzed in detail. Assessment of T-cell responses and I-Ad binding capacity of position 446-substituted analogs of an IgG2a allotype b (IgG2a(b)) heavy chain peptide demonstrates that engagement of the P9 pocket is crucial for effective peptide presentation. Sidechain size rather than charge decides the capacity to engage the P9 pocket. Thus, small, uncharged sidechains are accepted, whereas acidic and aromatic amino acids as well as lysine and arginine are disfavored. The specificity of the P9 pocket of I-Ad (serine beta57) is distinct from that of the diabetes-associated I-Ag7 (aspartic acid beta57), supporting the contention that the polymorphism at residue beta57 influences diabetes susceptibility via P9-specific effects on the repertoires of self peptides presented to T cells. Furthermore, the data rationalize the susceptibility to HSV-induced keratitis conferred by the a and the protection conferred by the b allotypes of the IgG2a heavy chain. Keratitogenic T cells, which cross-react with the viral UL6 protein and a corneal antigen, are silenced in IgG2a(b) mice because of antigenic mimicry with gamma2a(b) 435-451. Our finding that the lysine P9 residue of the corresponding gamma2a(a) allopeptide precludes high-affinity binding to I-Ad indicates that the susceptibility of IgG2a(a) mice reflects inefficient thymic presentation of autologous IgG2a and thus failure to purge the T-cell repertoire of the pathogenic clones.
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PMID:The P9 peptide sidechain specificity of I-Ad. 1065 74

Type 1 diabetes mellitus in nonobese diabetic (NOD) mice, a well-known model of human type 1 diabetes, has been considered to be caused by the destruction of insulin-producing beta cells in the islets of the pancreas by self-reactive T cells. Antigen-presenting cells like dendritic cells (DCs) and macrophages are expected to be involved in the processes from their role in generating regulatory or effector T cells. These immunohistochemical studies revealed that CD11c-positive DCs already appeared in the islets of NOD mice as early as 4 weeks old when lymphocytes were not yet infiltrated in the islet, and thus insulitis was not developed. DCs were first observed to locate around swollen parainsular vessels. From age 7 weeks onward to age 13 weeks, more DCs were present in parainsular areas where lymphocytes had also accumulated, and the number of DCs in the islets as well as lymphocytes increased. However, at the end stage of insulitis from age approximately 17 weeks onward, the number of DCs in the islets decreased. In contrast, accumulation of DCs in the para- and periislets was not observed in 7- and 17-week-old ICR female mice that do not develop type 1 diabetes. Double-staining studies using confocal laser scanning microscopy showed that the CD11c-positive DCs coexpress both major histocompatibility (MHC) class II and costimulatory molecules, CD80 and CD86. Electron-microscopy studies further demonstrated that cell bodies and processes of the DCs make close contact with lymphocytes. These results suggest that DCs infiltrated into the pancreatic islets are capable of stimulating T cells by the MHC class II-antigenic peptide complex, together with costimulatory molecules, which eventually lead to the beta-cell destruction in NOD mice.
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PMID:In situ characterization of dendritic cells occurring in the islets of nonobese diabetic mice during the development of insulitis. 1076 56


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