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)

Infectious disease has been proposed as an environmental modifier of autoimmunity in both human populations and the NOD mouse. We found that infection of NOD mice with attenuated, but not killed, Salmonella typhimurium can reduce the incidence of type 1 diabetes (T1D), even if infection occurs after the development of a peri-islet pancreatic infiltrate. Functional diabetogenic effector T cells are still present, as demonstrated by the initiation of diabetes in NOD-scid recipients of transferred splenocytes. High levels of IFN-gamma are secreted by splenocytes of infected mice, but there is no evidence of involvement of IL-10 in the protective effect of the infection. Finally, prolonged changes in cell subsets are observed in infected mice involving invariant Valpha14Jalpha281 NuKappaTau and dendritic cells. These data reinforce the idea that prevention of T1D in the NOD mouse cannot be reduced to the simple Th1/Th2 paradigm and that different infections may involve different protective mechanisms.
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PMID:Salmonella typhimurium infection halts development of type 1 diabetes in NOD mice. 1537 94

Glutamic acid decarboxylase (GAD) 65 is one of the major pancreatic antigens targeted by self-reactive T cells in type I diabetes mellitus. T cells specific for GAD65 are among the first to enter inflamed islets and may be important for the initiation of autoimmune diabetes. However, we previously reported that nonobese diabetic (NOD) mice transgenic for a T cell antigen receptor (TCR) specific for one of the immunodominant epitopes of GAD65, peptide 286-300 (G286), are protected from insulitis and diabetes. To examine whether other GAD65-reactive T cells share this phenotype, we have generated TCR transgenic NOD mice for a second immunodominant epitope of GAD65, peptide 206-220 (G206). As in G286 mice, G206 mice do not develop islet inflammation or diabetes. When adoptively transferred along with diabetogenic T cells, activated G206 T cells significantly delayed the onset of diabetes in NOD.scid recipients. Both G206 and G286 T cells produce immunoregulatory cytokines IFN-gamma and IL-10 at low levels when activated by cognate antigens. These data suggest that GAD65-specific T cells may play a protective role in diabetes pathogenesis by regulating pathogenic T cell responses. A better understanding of the functions of autoreactive T cells in type I diabetes will be necessary for choosing desirable targets for immunotherapy.
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PMID:Prevention of type I diabetes transfer by glutamic acid decarboxylase 65 peptide 206-220-specific T cells. 1538 70

Immunization of NOD mice with autoantigens such as glutamic acid decarboxylase (GAD) 221-235 peptide (p221) can induce Ag-specific CD4(+) T regulatory (Tr) cells. However, it is unclear whether these Tr cells acquire their regulatory capacity due to immunization or whether they are constitutively harbored in unimmunized naive mice. To address this question, we used an I-Ag7 tetramer to isolate p221-specific T cells from naive NOD mice (N221(+) cells) after peptide-specific in vitro expansion. The N221(+) T cells produced IFN-gamma and IL-10, but very little IL-4, in response to p221 stimulation. These T cells could function as regulatory cells and inhibit in vitro proliferation of diabetogenic BDC2.5 cells. This suppressive activity was cell contact-independent and was abrogated by Abs to IL-10 or IL-10R. Interestingly, IL-2 produced by other T cells present in the cell culture induced unactivated N221(+) T cells to exhibit regulatory activities involving production of IL-10. In vivo, N221(+) cells inhibited diabetes development when cotransferred with NOD splenocytes into NOD/scid recipients. Together, these results demonstrate that p221-specific IL-10-dependent Tr cells, including Tr type 1 cells, are present in naive NOD mice. The use of spontaneously arising populations of GAD peptide-specific Tr cells may represent a promising immunotherapeutic approach for preventing type 1 diabetes.
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PMID:Presence of diabetes-inhibiting, glutamic acid decarboxylase-specific, IL-10-dependent, regulatory T cells in naive nonobese diabetic mice. 1555 71

Abundant evidence suggests that cytokines involve in the pathogenesis of latent autoimmune diabetes of adults (LADA). This is a slowly progressive form of type 1 diabetes, which is initially diagnosed as type 2 diabetes. In this study, healthy individuals LADA and type 2 diabetic patients were genotyped for IL-6-174G/C, TNF-alpha-308A/G, TGF-beta1-codon10T/C, TGF-beta1-codon25G/C, IL-10-1082A/G, IL-10-819T/C, IL-10-592A/C gene polymorphisms, by sequence-specific-primer polymerase chain reaction methodology. A significant difference in the frequencies of -1082A/G IL-10 alleles was observed, with the -1082*A allele (known to be associated with low IL-10 production), predominating in LADA diabetics than type 2 diabetics (p=0.036). No significant differences of genotypes, phenotypes, or haplotype frequencies in the remaining cytokine polymorphisms were observed. Analysis of allele combinations revealed a significant involvement of the low and high in vitro production IL-10 alleles in the development of LADA and type 2 diabetes, respectively. These results suggest that the G/A mutation at position -1082 of IL-10 promoter gene region might be one of the factors participating to the pathogenesis of LADA diabetes and that identification of cytokine gene polymorphisms might contribute to the characterization of the different types of diabetes mellitus.
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PMID:TNF-alpha, TGF-beta1, IL-10, IL-6, gene polymorphisms in latent autoimmune diabetes of adults (LADA) and type 2 diabetes mellitus. 1562 43

NKT cells are potent regulatory T cells that prevent the development of several autoimmune diseases. Analysis of NKT cell regulatory function in the NOD mouse has revealed that NKT cells inhibit the development of type 1 diabetes by impairing the differentiation of anti-islet T cells into Th1 effector cells. In the present study, we have performed in vitro and in vivo experiments to determine the respective role of cytokines and cell contacts in the blockade of T cell differentiation by NKT cells. These experiments reveal that cytokines such as IL-4, IL-10, IL-13, and TGF-beta, that have been involved in other functions of NKT cells, play only a minor role if any in the blockade of T cell differentiation by NKT cells. Diabetes is still prevented by NKT cells in the absence of functional IL-4, IL-10, IL-13, and TGF-beta. In contrast, we show for the first time that cell contacts are crucial for the immunoregulatory function of NKT cells.
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PMID:Inhibition of T cell differentiation into effectors by NKT cells requires cell contacts. 1569 23

Achieving immunologic tolerance to autoimmune diabetes is the goal of therapies for treatment and prevention of the disease. However, whether this can be achieved with an antigen-specific approach is still unproven in humans. Other approaches, including treatment with anti-CD3 monoclonal antibody, have focused on regulation of an active immune response. Preclinical studies with anti-CD3 mAb showed the ability to reverse diabetes and induce tolerance to autoimmunity, even at the time of presentation with hyperglycemia. These studies also suggested that mAb treatment induced an active regulatory process. Based on these and other preclinical data, we have carried out a Phase I/II trial of the humanized FcR non-binding anti-CD3 mAb hOKT3gamma1(Ala-Ala) in patients with new-onset type 1 diabetes. mAb treatment prevented the loss of insulin production over the first two years of the disease with reduced hemoglobin A1c levels and insulin usage. Studies have suggested that the mechanism of drug action involves induction of regulatory cells. CD4(+)IL-10(+) T cells can be found in patients after treatment; in addition, the CD8(+) T cells are induced by the mAb, and these cells may regulate antigen- specific responses. These initial studies have shown clinical efficacy of treatment with anti-CD3 mAb and suggest a novel mechanism that may account for the lasting effects of treatment.
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PMID:Use of anti-CD3 monoclonal antibody to induce immune regulation in type 1 diabetes. 1569 86

This work aims to evaluate the potential use of insulin-like growth factor 2 (IGF-2) as the dominant thymic self-antigen precursor of the insulin family in designing a tolerogenic approach to type 1 diabetes (T1D) prevention. This evaluation was primarily based on cytokine profile driven by MHC presentation of insulin and IGF-2-derived antigens to PBMC cultures derived from 16 T1D DQ8(+) adolescents. Insulin B9-23, one dominant beta-cell autoantigen, and the homologous sequence B11-25 of IGF-2 display the same affinity and fully compete for binding to DQ8, a MHC-II allele conferring major genetic susceptibility to type 1 diabetes (T1D). However, compared to insulin B9-23, presentation of IGF-2 B11-25 elicits a suppressive/regulatory cytokine profile with a higher number of IL-10-secreting cells (P < 0.05), a much higher ratio of IL-10/IFN-gamma (P < 0.01), as well as a lower number of IL-4-secreting cells (P < 0.05). Thus, with regard to T1D prevention, administration of IGF-2-derived self-antigen(s) seems to be an efficient approach that combines both antagonism for binding to a major susceptibility MHC-II allele, as well as downstream promotion of an antigen-driven tolerogenic response.
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PMID:An insulin-like growth factor 2-derived self-antigen inducing a regulatory cytokine profile after presentation to peripheral blood mononuclear cells from DQ8+ type 1 diabetic adolescents: preliminary design of a thymus-based tolerogenic self-vaccination. 1569 93

Prevention of type 1 diabetes mellitus requires early intervention in the autoimmune process directed against beta cells of the pancreatic islets of Langerhans. This autoimmune inflammatory process is thought to be caused by the effect of Th1 cells and their secreted cytokines (e.g. interferon) and to be suppressed by Th2-secreted anti-inflammatory cytokines (e.g. IL-4, IL-10). Various methods aimed specifically at halting or modulating this response have been attempted. An alternative method is the re-induction of tolerance towards the putative self antigen that causes the disease. Proposed antigens such as insulin, glutamic acid decarboxilase (GAD) and the heat shock protein 60 (Hsp60)-derived peptide 277 have been used successfully in murine diabetes models and in initial clinical trials in early diabetes patients. Here, we review the results of these trials.
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PMID:Immune modulation for prevention of type 1 diabetes mellitus. 1573 55

Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine that plays a pivotal role in several immunoinflammatory and autoimmune diseases. In this study we examined the role of MIF in the development of immunoinflammatory diabetes induced in susceptible strains of mice by multiple low doses of streptozotocin. We found that MIF protein was significantly elevated in islet cells during the development of diabetes, and that targeting MIF activity with either neutralizing antibody or the pharmacological inhibitor (S,R)-3-(4-hydroxyphenyl)-4,5-dihydro-5-isoxazole acetic acid methyl ester, markedly reduced clinical and histopathological features of the disease, such as hyperglycemia and insulitis. Lymphocytes from mice treated with the MIF inhibitors exhibited reduction of both islet antigen-specific proliferative responses and adhesive cell-cell interactions. Neutralization of MIF also down-regulated the ex vivo secretion of the proinflammatory mediators, TNF-alpha, interferon-gamma, and nitric oxide, while augmenting that of the antiinflammatory cytokine, IL-10. This study provides the first in vivo evidence for a critical role for MIF in the immune-mediated beta-cell destruction in an animal model of human type 1 diabetes mellitus and identifies a new therapeutic strategy for the prevention and treatment of this disease in humans that is based on the selective inhibition of MIF activity.
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PMID:Critical role of macrophage migration inhibitory factor activity in experimental autoimmune diabetes. 1579 Jul 30

Natural CD4(+)CD25(+) regulatory T (CD4(+)CD25(+) T reg) cells play a key role in the immunoregulation of autoimmunity. However, little is known about the interactions between CD4(+)CD25(+) T reg cells and autoreactive T cells. This is due, in part, to the difficulty of using cell surface markers to identify CD4(+)CD25(+) T reg cells accurately. Using a novel real-time PCR assay, mRNA copy number of FoxP3, TGFbeta1, and interleukin (IL)-10 was measured in single cells to characterize and quantify CD4(+)CD25(+) T reg cells in the nonobese diabetic (NOD) mouse, a murine model for type 1 diabetes (T1D). The suppressor function of CD4(+)CD25(+)CD62L(hi) T cells, mediated by TGFbeta, declined in an age-dependent manner. This loss of function coincided with a temporal decrease in the percentage of FoxP3 and TGFbeta1 coexpressing T cells within pancreatic lymph node and islet infiltrating CD4(+)CD25(+)CD62L(hi) T cells, and was detected in female NOD mice but not in NOD male mice, or NOR or C57BL/6 female mice. These results demonstrate that the majority of FoxP3-positive CD4(+)CD25(+) T reg cells in NOD mice express TGFbeta1 but not IL-10, and that a defect in the maintenance and/or expansion of this pool of immunoregulatory effectors is associated with the progression of T1D.
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PMID:Single cell analysis shows decreasing FoxP3 and TGFbeta1 coexpressing CD4+CD25+ regulatory T cells during autoimmune diabetes. 1583 17


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