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)

The generation of auto-aggressive T cells involves failure of central or peripheral tolerance. We previously demonstrated that peripheral CD4(lo)CD40(+) T cells give rise to pathogenic T cells in the non-obese diabetic (NOD) model. Here we show that peripheral CD4(+)CD40(+) T cells from diabetic or pre-diabetic NOD mice induce insulin-dependent diabetes mellitus. Consistent with breach of peripheral tolerance, CD4(lo)CD40(+) T cells expand with age in NOD mice but not in MHC-matched non-obese resistant (NOR) or BALB/c controls. Suggestive of a causal role for CD40 in autoimmunity, blocking CD40-CD154 interactions early during NOD development prevents autoaggressive T cell expansion while promoting increases in CD4(+)CD25(+) regulatory T cells. Importantly, CD40 signals promote expansion of V alpha 3.2(+) and V alpha 8.3(+) T cells. Furthermore, peripheral V alpha 3.2(+)CD40(+) T cells induce diabetes in NOD.scid recipients while V alpha 8.3(+) T cells or V alpha 3.2(+)-depleted T cell populations do not. This is the first demonstration that primary T cells transfer disease with the kinetics of auto-aggressive T cell clones and that specific TCR V alpha expansion promotes diabetes.
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PMID:Peripheral CD4loCD40+ auto-aggressive T cell expansion during insulin-dependent diabetes mellitus. 1511 83

Cellular immunologic tests have not been used for diagnostic purposes in individuals at risk for autoimmune insulitis or in patients with partial beta-cell destruction because of a lack of studies that show their predictive value. In this study we initially evaluated 43 patients with recent-onset Type 1 diabetes (disease duration <or= 6 months, 29 ICA positive) with regard to beta-cell secretion stimulation test with glucagon and immunologic parameters, including CD4 +, CD8 +, CD4 + CD25 +, CD8 + CD25 + lymphocyte subsets. At baseline, C-peptide concentration 6 min after stimulation increased on average by 0.18 +/- 0.27 micro g/ml. The percentage of CD4 + cells was 42 +/- 9,4 % (healthy controls 44 +/- 7.3 %, p nonsig.) and percentage of CD8 + was 33 +/- 8.6 % (healthy control 31 +/- 8.3 %, p nonsig.). Relative size of CD4 + CD25 + subpopulation was 7 +/- 5.4 % (healthy control 2 +/- 2 %, p < 0.001). Percentage of activated CD8 + cell subset was also increased (2 +/- 1.4 vs. 1.0 +/- 1.0 %), but not significantly. Functional beta-cell testing was repeated after 6 months and nineteen patients were eligible for analysis. Their response was weaker after 6 months (0.13 +/- 0.1 micro g/ml, p < 0.05 vs. baseline). The average change in C-peptide excursion from baseline to the endpoint was - 0.07 +/- 0.17 micro g/ml. There was no significant correlation between beta-cell functional parameters at baseline (C-peptide6min (baseline)) and the relative size of various T cell subpopulations. Results were identical for the 6-month beta-cell functional data (C-peptide6min (6month)). The change in the excursion of C-peptide between baseline and follow-up visit (C-peptide6min (6month-baseline)) showed mild, negative correlation with relative size of the CD8 + CD25 + subpopulation (r = - 0.511, p = 0.025), which may indicate that the size of this cell subpopulation has predictive value in assessing future functional beta-cell changes.
Exp Clin Endocrinol Diabetes 2004 Apr
PMID:Beta-cell secretory function and CD25 + lymphocyte subsets in the early stage of type 1 diabetes mellitus. 1512 21

Because abnormalities in redox balance cluster in type I diabetes families and the intracellular thiol redox status seems to modulate immune function, we aimed to investigate the relationship between oxidative stress and immunological features. We measured oxidative markers, serum proinflammatory cytokines, soluble cytokine receptors and subsets of peripheral blood lymphocytes (by varying combinations of CD4, CD8, CD23 or low-affinity IgE receptor, and CD25 or IL-2 receptor) from 38 type I patients, 76 low-risk (i.e. without underlying islet autoimmunity) non-diabetic first-degree relatives of diabetic patients, and 95 healthy subjects. In type I diabetes families, protein and lipid oxidation was confirmed by the presence of reduced sulphhydryl groups, increased advanced oxidation protein products, and increased plasma and erythrocyte malondialdehyde. Relatives had decreased counts of monocytes, of cells co-expressing CD23 and CD25 and of CD25(+) cells in peripheral blood. Patients with TIDM had similar defects and, in addition, showed decreased counts of peripheral CD4(+)CD8(+) lymphocytes and increased serum levels of soluble receptors for interleukin (IL)-6 and IL-2. Abnormal indicators of oxidative stress were related in part to immune abnormalities. In the whole study group, we found a correlation (multiple R 0.5, P < 0.001) of CD23(+)CD25(+) cells with blood counts of monocytes, CD4(+)CD8(+) cells, CD25(+) cells, basal haemolysis and plasma levels of thiols. In type I diabetics, anti-GAD65 antibody levels were associated (multiple R 0.6, P = 0.01) positively with sIL-6R, negatively with duration of diabetes and CD23(+)CD25(+) counts; plasma creatinine correlated positively (multiple R 0.6, P < 0.001) with both sIL-2R and tumour necrosis factor (TNF)-alpha concentration. Our study reports the first evidence that the oxidative stress observed in type I families is related to immunological hallmarks (decreased peripheral numbers of monocytes as well as cells bearing a CD4(+)CD8(+), CD23(+)CD25(+) and CD25(+) phenotype) from which the involvement of some immunoregulatory mechanisms could be suspected. It remains to be elucidated the course of events culminating in the loss of physiological immune homeostasis and disease pathology.
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PMID:Redox status and immune function in type I diabetes families. 1514 59

TNF/CD80 mice, a CD8(+) T cell-mediated model for type 1 diabetes, transgenically express tumor necrosis factor alpha (TNF-alpha) and the costimulatory molecule CD80 in their pancreatic islets. Here we show that these molecules bypass the need for CD40-CD154 costimulatory interactions in activation of CD8(+) T cells, allowing us to determine the role of CD40-CD154 signals in regulation of autoaggressive CD8(+) T cells after their in vivo priming. TNF/CD80 CD154-deficient mice rapidly develop diabetes, whereas CD154-sufficient mice do not. This finding correlates with the decreased numbers of CD4(+)CD25(+) T regulatory (T(R)) cells in the islets and pancreatic lymph nodes, in comparison to disease-protected CD154-sufficient mice. Administration of a CD40 agonistic antibody induces a systemic and tissue-specific increase in T(R) cells. However, this increase fails to delay diabetes development in the absence of CD154. Adoptive transfer studies show that CD8(+) T cells from TNF/CD80 CD154-deficient, but not CD154-sufficient, mice are resistant to regulation in vivo. This study provides evidence that CD40-transduced signals initiate T(R) cell increase in vivo and that CD154-transduced signals sensitize autoaggressive CD8(+) T cells to suppression.
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PMID:CD154 is a negative regulator of autoaggressive CD8+ T cells in type 1 diabetes. 1519 49

Adoptive transfer of ovalbumin (OVA)-specific T cells from the DO.11 TCR transgenic mouse on a Rag(-/-) background into mice expressing OVA in pancreatic islet cells induces acute insulitis and diabetes only if endogenous lymphocytes, including regulatory T cells, are removed. When wild-type OVA-specific/Rag(-/-) T cells, which are all CD25(-), are transferred into islet antigen-expressing mice, peripheral immunization with OVA in adjuvant is needed to induce diabetes. In contrast, naive CTLA-4(-/-)/Rag(-/-) OVA-specific T cells (also CD25(-)) develop into Th1 effectors and induce disease upon recognition of the self-antigen alone. These results suggest that CTLA-4 functions to increase the activation threshold of autoreactive T cells, because in its absence self-antigen is sufficient to trigger autoimmunity without peripheral immunization. Further, CTLA-4 and regulatory T cells act cooperatively to maintain tolerance, indicating that the function of CTLA-4 is independent of regulatory cells, and deficiency of both is required to induce pathologic immune responses against the islet self-antigen.
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PMID:Cooperative roles of CTLA-4 and regulatory T cells in tolerance to an islet cell antigen. 1521 Jul 48

Dietary gluten has been associated with an increased risk of type 1 diabetes. We have evaluated inflammation and the mucosal immune response to gliadin in the jejunum of patients with type 1 diabetes. Small intestinal biopsies from 17 children with type 1 diabetes without serological markers of celiac disease and from 50 age-matched control subjects were examined by immunohistochemistry. In addition, biopsies from 12 type 1 diabetic patients and 8 control subjects were cultured with gliadin or ovalbumin peptic-tryptic digest and examined for epithelial infiltration and lamina propria T-cell activation. The density of intraepithelial CD3(+) and gammadelta(+) cells and of lamina propria CD25(+) mononuclear cells was higher in jejunal biopsies from type 1 diabetic patients versus control subjects. In the patients' biopsies cultured with peptic-tryptic gliadin, there was epithelial infiltration by CD3(+) cells, a significant increase in lamina propria CD25(+) and CD80(+) cells and enhanced expression of lamina propria CD54 and crypt HLA-DR. No such phenomena were observed in control subjects, even those with celiac disease-associated HLA haplotypes. In conclusion, signs of mucosal inflammation were present in jejunal biopsies from type 1 diabetic patients, and organ culture studies indicate a deranged mucosal immune response to gliadin.
Diabetes 2004 Jul
PMID:In vitro-deranged intestinal immune response to gliadin in type 1 diabetes. 1522 Jan 90

It is well established that CD4(+)CD25(+) regulatory T cells (Tregs) inhibit autoimmune pathology. However, precisely how the behavior of disease-inducing T cells is altered by Tregs remains unclear. In this study we use a TCR transgenic model of diabetes to pinpoint how pathogenic CD4 T cells are modified by Tregs in vivo. We show that although Tregs only modestly inhibit CD4 cell expansion, they potently suppress tissue infiltration. This is associated with a failure of CD4 cells to differentiate into effector cells and to up-regulate the IFN-gamma-dependent chemokine receptor CXCR-3, which confers the ability to respond to pancreatic islet-derived CXCL10. Our data support a model in which Tregs permit T cell activation, yet prohibit T cell differentiation and migration into Ag-bearing tissues.
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PMID:CD4+CD25+ cells controlling a pathogenic CD4 response inhibit cytokine differentiation, CXCR-3 expression, and tissue invasion. 1532 52

Autoimmune disease results from the dysregulation of basic tolerogenic processes designed to control self/non-self-discrimination. Approaches to treat autoimmunity have focused historically on potent immunosuppressives that block the activation and expansion of antigen-specific T cells before they differentiate into pathogenic T cell responses. These therapies are very efficient in reducing clonal expansion and altering early signaling pathways. However, once the pathogenic responses are established (i.e., autoimmunity), the interventions are less effective on activated and differentiated T cell subsets (including memory T cells) or acting in the presence of an inflammatory milieu to abort immune responses at the target tissue and systemically. Moreover, the current immunotherapies require continuous use because they do not redirect the immune system to a state of tolerance. The continuous treatment leads to long-term toxicities and can profoundly suppress protective immune responses targeted at viruses, bacteria, and other pathogens. Over the past decade, there have been tremendous advances in our understanding of the basic processes that control immune tolerance. Among the most exciting has been the identification of a professional regulatory T cell subset that has shown enormous potential in suppressing pathologic immune responses in autoimmune diseases, transplantation, and graft vs. host disease. In this review, we summarize current efforts to induce and maintain tolerance in the autoimmune diabetes setting by using therapeutic vaccination with CD4(+)CD25(+) regulatory T cells. Emphasis will be placed on approaches to exploit regulatory T cells either directly or through the use of anti-CD3 immunotherapy.
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PMID:Therapeutic vaccination using CD4+CD25+ antigen-specific regulatory T cells. 1532 72

Little is known about the fate of autoreactive CD4 T cells in blood. Using a mouse model for spontaneous autoimmune diabetes we demonstrated that the status of the autoimmune process in pancreas could be pictured through the frequency and phenotype of autoreactive CD4 T cells in the blood. Early during the prediabetic stage, the frequency of these cells in blood decreased as a consequence of their recruitment in the pancreas. This was followed by an imbalance between CD4(+)CD25(+) and CD4(+)CD69(+) T cells in the pancreas that was mirrored in the phenotype of autoreactive T cells in the blood. Waves of activated CD4(+)CD69(+) T cells in blood preceded the disease onset suggesting that the autoimmune attack on pancreas is a discontinuous "hit-and-run" rather than a continuous process. Tracking autoreactive CD4 T cells in blood may help in identifying prediabetic humans and monitoring the disease progression during therapeutic interventions.
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PMID:Immunokinetics of autoreactive CD4 T cells in blood: a reporter for the "hit-and-run" autoimmune attack on pancreas and diabetes progression. 1532 33

Converging experimental evidence indicates that CD4(+) regulatory T cells control progression of autoimmune insulitis in nonobese diabetic (NOD) mice. Here, we studied the nature of these regulatory T cells and their mode of action in diabetes-prone NOD Rag(-/-) or severe combined immunodeficient (SCID) mice harboring a transgenic T cell receptor derived from the diabetogenic T cell clone BDC2.5. We first show that diabetes onset is prevented in such mice by infusion of polyclonal CD4(+) T cells expressing L-selectin (CD62L) but not prevented or only marginally prevented by CD4(+)CD25(+) T cells. Similarly, we found with a cotransfer model that CD4(+)CD62L(+) T cells but not CD4(+)CD25(+) T cells inhibited diabetes transfer into NOD SCID recipients by transgenic NOD BDC2.5 SCID cells. Unexpectedly, cotransfer of transgenic NOD BDC2.5 SCID cells and spleen cells from WT diabetic NOD mice did not induce diabetes, whereas each individual population did so. Data are presented arguing for the role of CD4(+)CD62L(+) T cells present within the polyclonal diabetogenic population in mediating this apparently paradoxical effect. Collectively, these data confirm the central role of CD4(+)CD62L(+) regulatory T cells in controlling disease onset in a well defined transgenic model of autoimmune diabetes and suggest the intervention of homeostatic mechanisms as part of their mode of action.
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PMID:Unique role of CD4+CD62L+ regulatory T cells in the control of autoimmune diabetes in T cell receptor transgenic mice. 1534 Jan 48


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