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)

Various defects in antigen-presenting cells (APCs) and T-cells, including regulatory cells, have been associated with type 1 diabetes development in NOD mice. CD4(+)CD25(+) regulatory cells play a crucial role in controlling various autoimmune diseases, and a deficiency in their number or function could be involved in disease development. The current study shows that NOD mice had fewer CD4(+)CD25(+) regulatory cells, which expressed normal levels of glucocorticoid-induced tumor necrosis factor receptor and cytotoxic T-lymphocyte-associated antigen-4. We have also found that NOD CD4(+)CD25(+) cells regulate poorly in vitro after stimulation with anti-CD3 and NOD APCs in comparison with B6 CD4(+)CD25(+) cells stimulated with B6 APCs. Surprisingly, stimulation of NOD CD4(+)CD25(+) cells with B6 APCs restored regulation, whereas with the reciprocal combination, NOD APCs failed to activate B6 CD4(+)CD25(+) cells properly. Interestingly, APCs from disease-free (>30 weeks of age), but not diabetic, NOD mice were able to activate CD4(+)CD25(+) regulatory function in vitro and apparently in vivo because only spleens of disease-free NOD mice contained potent CD4(+)CD25(+) regulatory cells that prevented disease development when transferred into young NOD recipients. These data suggest that the failure of NOD APCs to activate CD4(+)CD25(+) regulatory cells may play an important role in controlling type 1 diabetes development in NOD mice.
Diabetes 2006 Jul
PMID:Deficiency in NOD antigen-presenting cell function may be responsible for suboptimal CD4+CD25+ T-cell-mediated regulation and type 1 diabetes development in NOD mice. 1680 81

During the past 10 years, CD4(+)CD25(+)Foxp3(+) regulatory T cells (Treg) have been extensively studied for their function in autoimmune disease. This review summarizes the evidence for a role of Treg in suppression of innate and adaptive immune responses in experimental models of autoimmunity including arthritis, colitis, diabetes, autoimmune encephalomyelitis, lupus, gastritis, oophoritis, prostatitis, and thyroiditis. Antigen-specific activation of Treg, but antigen-independent suppressive function, emerges as a common paradigm derived from several disease models. Treg suppress conventional T cells (Tcon) by direct cell contact in vitro. However, downmodulation of dendritic cell function and secretion of inhibitory cytokines such as IL-10 and TGF-beta might underlie Treg function in vivo. The final outcome of autoimmunity vs tolerance depends on the balance between stimulatory signals (Toll-like receptor engagement, costimulation, and antigen dose) and inhibitory signals from Treg. Whereas most experimental settings analyze the capacity of Treg to prevent onset of autoimmune disease, more recent efforts indicate successful treatment of ongoing disease. Thus, Treg are on the verge of moving from experimental animal models into clinical applications in humans.
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PMID:Regulatory T cells in experimental autoimmune disease. 1683 80

We previously reported that retrovirally mediated gene expression of Ig fusion proteins leads to specific immunologic tolerance and successful treatment of autoimmune conditions. Thus, a single dose of GAD65-IgG- or (Pro) Insulin-IgG-transduced B cells delays the onset and decreases the incidence of diabetes in young (7-12 weeks old) NOD female mice. Herein, we tested the role of regulatory T cells by in vivo treatment with anti-CD25 before B-cell gene therapy or by in vitro ablation of CD25+ cells from tolerized hosts in an adoptive transfer model. Our results demonstrate that anti-CD25 treatment, like cyclophosphamide, partially blocks the efficacy of gene therapy for tolerance. Moreover, B-cell therapy is effective at preventing diabetes transfer by female T cells (from older diabetic mice) into intact male recipients with normal islets, but failed to do so in NOD-scid recipients. This is due in part to homeostatic proliferation but also to the absence of CD25+ T cells in the latter hosts. Tolerance induced in younger NOD females can be stably transferred to NOD-scid recipients. However, physical removal of CD25+ cells abrogates the transfer of tolerance. Therefore, we conclude that CD4+, CD25+ regulatory T cells are required for the induction as well as maintenance of tolerance in this gene therapy model. The phenotype of these induced regulatory T cells is under investigation.
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PMID:Treatment of diabetes in NOD mice by gene transfer of Ig-fusion proteins into B cells: role of T regulatory cells. 1686 Feb 96

Antigen stimulation of immune cells activates the transcription factor NFAT, a key regulator of T cell activation and anergy. NFAT forms cooperative complexes with the AP-1 family of transcription factors and regulates T cell activation-associated genes. Here we show that regulatory T cell (Treg) function is mediated by an analogous cooperative complex of NFAT with the forkhead transcription factor FOXP3, a lineage specification factor for Tregs. The crystal structure of an NFAT:FOXP2:DNA complex reveals an extensive protein-protein interaction interface between NFAT and FOXP2. Structure-guided mutations of FOXP3, predicted to progressively disrupt its interaction with NFAT, interfere in a graded manner with the ability of FOXP3 to repress expression of the cytokine IL2, upregulate expression of the Treg markers CTLA4 and CD25, and confer suppressor function in a murine model of autoimmune diabetes. Thus by switching transcriptional partners, NFAT converts the acute T cell activation program into the suppressor program of Tregs.
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PMID:FOXP3 controls regulatory T cell function through cooperation with NFAT. 1687 58

Non-hypercalcemic analogs of vitamin D(3) modulate the immune response through antigen-presenting cells (APCs) and activated T-cells. A large population-base case-control showed that vitamin D(3) intake significantly decreases the risk of type 1 diabetes development. The aim of this study was, therefore, to observe the in vivo effects of a vitamin D(3) analog administered to Bio Breeding (BB) rats. 1,25-Dihydroxy-16,23Z-diene-26,27-hexafluoro-19-nor vitamin D(3) (BXL-219, formerly Ro 26-2198) (BioXell, Milan, Italy) was administered in vivo to BB rats from days 42 to 110 of life at 0.2 microg/Kg BW. Control animals received only vehicle (olive oil, 4.8 microl/100 g BW). The animals of these two groups were subjected to insulin treatment as they became diabetic. Insulin (Humulin, 28.6 UI/day) was administered irrespective of diabetes occurrence to another group of rats for comparison. Blood glucose, insulin levels, glycosuria, degree of islet infiltration, and the expression of some antigens were observed. Results showed that the vitamin D(3) analog reduced diabetes incidence, although limitedly, in BB rats while administration of oral insulin increased diabetes incidence. In addition, the vitamin D(3) analog did not stimulate an enhancement in the expression of CD4 and CD25 in BB rats as it does in NOD mice, which may explain the failure of this as well as other antidiabetic treatments in the BB animal model of type 1 diabetes.
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PMID:Effects of a vitamin D3 analog on diabetes in the bio breeding (BB) rat. 1696 Aug 73

The Bio Breeding (BB) rat is a useful animal model of type 1 autoimmune diabetes. The aim of this study was to observe and follow the cytokine and antigenic expressions within the islets of Langerhans in young non-diabetic, in pre-diabetic hyperglycemic, and in overtly diabetic animals. BB rats were therefore checked at day 21 up to day 90 of life for blood glucose, insulin levels, degree of islet infiltration, expression of proinflammatory and protective cytokines and antibodies including CD4, CD8, CD25, LFA-1, and ICAM-1. Animals were treated with insulin as they became diabetic. We found that islets of non-diabetic BB rats became positive to both IL-1beta and IL-4 very early on, confirming a local but intense production of both cytokines within the islets during the initial non-diabetic period. In addition, we observed that the production of these interleukins together with the expression levels of CD4 and CD25 are events predictive for type 1 diabetes onset in non-diabetic BB rats, as for non-obese diabetic (NOD) mice. In particular, the production of IL-1beta and IL-4 during the non-diabetic period together with the lack of enhancement of CD4 and CD25, indicating selective recruitment of activated T cells, may explain the failure of anti-diabetic treatments in this animal model of type 1 diabetes.
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PMID:An early but intense cytokine production within the islets may be predictive for type 1 diabetes occurrence in the Bio Breeding (BB) rat. 1697 62

The latent autoimmune diabetes in adults (LADA) is a subgroup of type 1 diabetes, which procession of autoimmune destruction of beta-cells was slower than classic type 1 diabetes. To investigate the pathogenesis of LADA, we examined the lymphocyte subsets including the CD4(+)CD25(+) T-cells in 60 LADA patients and 30 patients of type 2 diabetes and 30 healthy individuals by FACS. And we compared the expression of FOXP3 mRNA in CD4(+) T-cell between 10 patients of LADA and 10 matched healthy individuals by real time PCR. The percent of CD4(+)CD25(+) T-cells were higher (11.89+/-4.96% versus 8.16+/-3.65%, P<0.01), and the percent CD8(+) T-cells elevated (24.58+/-6.80% versus 19.39+/-7.12, P<0.01) in LADA patients than healthy individuals. While the expression of FOXP3 mRNA in CD4(+) T-cell was markedly decreased in LADA patients (0.52-fold, n=10, P=0.004) compared with normal subjects. In addition, the percent of CD8(+) T-cells related with GAD-Ab titers in LADA patients (r=0.292, P=0.03). Our results showed that there were cellular immune disorder and decreased CD4(+) regulatory T-cells in LADA patients. The adoptive transfer regulatory T-cells seem to be a potential therapeutics for LADA.
Diabetes Res Clin Pract 2007 Apr
PMID:The CD4(+) regulatory T-cells is decreased in adults with latent autoimmune diabetes. 1700 88

Cellular interactions promoting the in vivo expansion of CD4(+)CD25(+)Foxp3(+) regulatory T (Treg) cells for maintenance of immune tolerance remain poorly defined. Here we report that mobilized Lin(-)Sca-1(+)c-kit(+) (LSK) hematopoietic progenitor cells (HPCs), unlike medullary hematopoietic stem cells (HSCs), selectively drove the direct, immediate expansion of functional host-derived Treg cells, thereby preventing the progression to overt spontaneous autoimmune diabetes in nonobese diabetic mice. Treg cell expansion required cell-to-cell contact and Notch3 signaling, which was mediated selectively through the Notch ligand Jagged2 expressed by the multipotent HPC subset, as assessed by small interfering RNA (siRNA) silencing. Conversely, notwithstanding their similar multilineage microchimerism, neither sorted Jagged2(-) HPCs nor Jagged2(lo) medullary HSCs were able to expand Treg cells. These data provide evidence for a productive Notch-mediated interaction between a unique subset of mobilized hematopoietic progenitors and Treg cells. They open therapeutic perspectives for autologous transplantation of Jagged2(+) LSK progenitors to promote Treg cell expansion in T cell-mediated diseases.
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PMID:Jagged2-expressing hematopoietic progenitors promote regulatory T cell expansion in the periphery through notch signaling. 1708 81

Maternal transmission of islet autoantibodies to children born to mothers with type 1 diabetes (T1D) has been shown to protect from autoantibodies and diabetes development later in life. However, the factors conferring disease protection are poorly understood. The aim of this study was to evaluate comparatively proinflammatory cytokines, autoantibodies and lymphocyte subsets in cord blood (CB) of children born to mothers with either T1D (n = 13), gestational diabetes (GDM) (n = 32) or healthy mothers (n = 81) in relation to transplacental passage of autoantibodies. The results are consistent with early priming of the fetal immune system only in children born to mothers with T1D. Levels of interleukin (IL)-1beta (P = 0.022), tumour necrosis factor (TNF)-alpha (P = 0.002) and IL-8 (P = 0.0012), as well as the frequency of CD4(+) CD25(+) T cells (P < 0.01) were significantly increased, and the increased levels correlated positively with anti-GAD65 autoantibody (GADA) levels. Moreover, CD4(+) CD25(+) T cells of children born to T1D mothers exhibited a more pronounced memory phenotype with increased CCR4 expression and down-regulation of CD62L. These data suggest that early activation of the fetal immune system as a consequence of maternal autoimmunity and transplacental passage of GADA may influence the generation and expansion of fetal regulatory T cells. This might induce an early antigen-specific immunological tolerance that could protect against T1D later in life.
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PMID:Evidence for immunological priming and increased frequency of CD4+ CD25+ cord blood T cells in children born to mothers with type 1 diabetes. 1710 Jul 70

The invariant (Ii) chain acts as an essential chaperone to promote MHC class II surface expression, Ag presentation, and selection of CD4(+) T cells. We have examined its role in the development of type 1 diabetes in NOD mice and show that Ii chain-deficient NOD mice fail to develop type 1 diabetes. Surprisingly, Ii chain functional loss fails to disrupt in vitro presentation of islet Ags, in the context of NOD I-A(g7) molecules. Moreover, pathogenic effector cells could be shown to be present in Ii chain-deficient NOD mice because they were able to transfer diabetes to NOD.scid recipients. The ability of these cells to transfer diabetes was markedly enhanced by depletion of CD25 cells coupled with in vivo anti-CD25 treatment of recipient mice. The numbers of CD4(+)CD25(+)Foxp3(+) T cells in thymus and periphery of Ii chain-deficient NOD mice were similar to those found in normal NOD mice, in contrast to conventional CD4(+) T cells whose numbers were reduced. This suggests that regulatory T cells are unaffected in their selection and survival by the absence of Ii chain and that an alteration in the balance of effector to regulatory T cells contributes to diabetes prevention.
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PMID:Loss of invariant chain protects nonobese diabetic mice against type 1 diabetes. 1711 28


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