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Query: UMLS:C0011849 (diabetes)
 277,896 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The thymus is the unique lymphoid organ inside which a confrontation occurs throughout life between neuroendocrine self-antigens and a recently evolved system with original recombination machinery driving random generation of immune response diversity. Through transcription of neuroendocrine genes in the thymus stromal network and expression of cognate receptors by immature T cells, the neuroendocrine system regulates early T cell differentiation. In addition and more specifically, intrathymic presentation of neuroendocrine self-antigens by, or in close association with, major histocompatibility complex (MHC) proteins is responsible for the establishment of central immune self-tolerance of neuroendocrine principles. All members of the insulin gene (INS) family are expressed in the thymus stroma according to a precise hierarchy and cell topography: IGF2 (thymic epithelial cells) > IGF1 (thymic macrophages) >> INS (thymic medullary epithelial cells and/or dendritic cells). Given this hierarchical pattern in gene expression, the protein IGF-2 is more tolerated than INS. Igf2 transcription is defective in the thymus of bio-breeding (BB) rat, one animal model of type 1 diabetes (T1DM). This thymus-specific defect in Igf2 expression may explain both the absence of central tolerance to INS-secreting beta cells and the lymphopenia (including lack of regulatory RT6(+) T cells) in diabetes-prone BB rats. INS B:9-23 and the homologous sequence of IGF-2 compete for binding to DQ8, an MHC class II allele conferring major susceptibility to T1DM. In young DQ8(+) T1DM patients, INS B:9-23 presentation by DQ8 elicits a dominant IFN-gamma secretion by isolated PBMCs, whereas presentation of the IGF-2 self-antigen promotes a dominant regulatory interleukin-10 secretion. These data demonstrate that opposite immune responses are driven by MHC presentation of a self-antigen (here, IGF-2) and an autoantigen (INS, as "altered" self). The important tolerogenic properties of thymic self-antigens deserve now to be exploited for prevention and/or cure of devastating autoimmune diseases such as T1DM.
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PMID:Role of the thymus in the development of tolerance and autoimmunity towards the neuroendocrine system. 1279 58

This study evaluates the local levels of proinflammatory cytokine, tumor necrosis factor alpha (TNF-alpha), and anti-inflammatory cytokine, interleukin-10 (IL-10), in an experimental buccal abscess of a diabetic rat model. We prepared a buccal cavity induced by injection of carrageenin in a diabetic rat (blood glucose, 460.6 +/- 54.7 mg/dl, mean +/- SE) induced by streptozotocin (STZ). The buccal abscess was formed by the direct inoculation of Streptococcus pyogenes S-8 (2 x 10(7) cfu) into the buccal cavity at day 5 after carrageenin injection. Cytokine levels in the exudate of the buccal abscess were measured by enzyme-linked immunosorbent assay for 48 h after infection. Bacterial counts, weighing of exudate, and histological analysis were also performed. The mean TNF-alpha levels in the buccal abscess exudate of the diabetic group, which were generally higher than those of the control group, tended to increase over time until 48 h after infection, while the TNF-alpha levels in the control group peaked at 24 h after infection and then decreased. The IL-10 levels in the diabetic group remained almost unchanged until 48 h after infection, while the IL-10 levels in the control group were significantly higher than in the diabetic group at 12-24 h after infection. The mean ratio of TNF-alpha to IL-10 levels was 1.17-1.67 in the diabetic group, which was higher than the 0.26-0.69 of the control group. The bacterial counts in the buccal abscess and the weight of exudate were significantly higher in the diabetic group compared to the control group at 36-48 h. Histological findings showed that inflammatory cell infiltration was remarkable in the diabetic group compared to that of the control group. These results suggest that the elevated proinflammatory TNF-alpha levels and decreased anti-inflammatory IL-10 levels, which are produced at local infection sites, may at least in part be related to the severity of inflammation in this rat model with diabetes induced by STZ.
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PMID:Balance of tumor necrosis factor alpha and interleukin-10 in a buccal infection in a streptozotocin-induced diabetic rat model. 1457 92

Anti-CD3 monoclonal antibodies (MAbs) were developed as a way of inducing immune suppression of T cells. More recent studies have indicated that anti-CD3 MAbs can affect immune responses by inducing immune regulation. We recently reported that a single course of treatment with a non-FcR binding anti-CD3 MAb, hOKT3gamma1(Ala-Ala), can lead to preservation of insulin production in patients with new-onset Type 1 diabetes for even beyond 1 yr after treatment. The sustained insulin production was accompanied by improvement in glucose control and reduced use of insulin. Our studies of the mechanism of the non-FcR binding anti-CD3 MAb indicate that the MAb delivers an activation signal to T cells resulting in disproportionate production of interleukin-10 (IL-10) relative to interferon-gamma(IFN-gamma) in vitro compared with FcR binding anti-CD3 MAb, and detectable levels of IL-10, IL-5, but rarely IFN-gamma or IL-2 in the serum after treatment. In addition, the drug induces a population of CD4+IL-10+ CCR4+ cells in vivo. Preclinical data suggest that anti-CD3 MAb induces a population of regulatory T cells that can prevent or lead to reversal of Type 1 diabetes. The induction of cells with a regulatory phenotype may account for the ability of anti-CD3 MAb to induce immune regulation.
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PMID:Treatment of Type 1 diabetes with anti-CD3 monoclonal antibody: induction of immune regulation? 1461 Feb 90

Type 1 diabetes is a heterogeneous autoimmune disease and is frequently associated with other organ-specific autoimmune diseases, including autoimmune thyroid disease (AITD). Type 1 diabetic patients with AITD are known to show distinct clinical and immunological features from patients without AITD. This study investigated whether interleukin-10 (IL-10) gene promoter region polymorphisms are associated with susceptibility to type 1 diabetes and AITD. The frequency of -1082G/A, -819C/T, and -592C/A polymorphisms was analyzed in 54 type 1 diabetic patients with AITD, 74 type 1 diabetic patients without AITD, 124 nondiabetic patients with AITD, and 107 healthy subjects in a case-control study. No significant differences on the allele and genotype frequencies of three polymorphisms were found not only in type 1 diabetic patients with AITD compared with normal controls, but also between nondiabetic patients with AITD and healthy controls. The distribution of IL-10 gene haplotypes was also similar between both patient groups and normal controls. These results suggest that IL-10 gene promoter region polymorphisms are not associated with genetic susceptibility to type 1 diabetes and AITD.
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PMID:Interleukin-10 gene promoter region polymorphisms in patients with type 1 diabetes and autoimmune thyroid disease. 1467 88

The MHC accounts for half of the genetic susceptibility to type 1 diabetes (T1D). Evidence suggests that an imbalance in Th1/Th2 responses may play a key role in the development of autoimmune diabetes. Since interleukin-10 (IL-10) modulates immune and inflammatory responses and has been implicated in many autoimmune diseases, it seemed interesting to examine whether IL-10 polymorphisms participate in diabetes predisposition. In fact, this is the first association study investigating the role of the IL- 10 polymorphisms in susceptibility to T1D in a Caucasian population. Three promoter polymorphisms (-1082G/A, -819C/T, -592C/A) and two CA-repeat microsatellites (IL-10R and IL-10G at -4 and -1.1 kb) were tested in a case-control study with 294 T1D patients and 574 healthy controls. Our results prove a minor role of IL-10 in the autoimmune diabetes risk, although we found the same association trend with IL-10G(*)12 allele as was previously observed for multiple sclerosis and rheumatoid arthritis.
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PMID:Interleukin-10 polymorphisms in Spanish type 1 diabetes patients. 1505 67

Type 1 diabetes is a T-cell-mediated disease that is associated with loss of immunological tolerance to self-antigens. The mechanisms involved in maintenance of peripheral tolerance include a specialized subset of regulatory T-cells (Treg) within the CD4(+)CD25(+) T-cell population, but the function and phenotype of these cells in type 1 diabetes have not been investigated. We hypothesized that a deficiency in the CD4(+)CD25(+) Treg population or its function could contribute to the lack of self-tolerance evident in patients with type 1 diabetes. We show that although levels of CD4(+)CD25(+) T-cells are normal in patients with recent-onset adult type 1 diabetes, the ability of the Tregs in this population to suppress T-cell proliferation during in vitro cocultures is markedly reduced compared with control subjects (P = 0.007). Moreover, in patients with type 1 diabetes, these cocultures display a more proinflammatory phenotype, with increased secretion of interferon-gamma (P = 0.005) and decreased interleukin-10 production (P = 0.03). These deficiencies may reflect a disturbance in the balance of the CD4(+)CD25(+) population, because in patients with type 1 diabetes, a higher proportion of these cells coexpress the early activation marker CD69 (P = 0.007) and intracellular CTLA-4 (P = 0.01). These data demonstrate deficiency in function of the CD4(+)CD25(+) Treg population that may influence the pathogenesis of type 1 diabetes.
Diabetes 2005 Jan
PMID:Defective suppressor function in CD4(+)CD25(+) T-cells from patients with type 1 diabetes. 1561 15

The evidence that human insulin-dependent diabetes mellitus (IDDM) is a T cell-mediated disease is well substantiated, and the use of transgenic technology to understand the Th1/Th2 paradigm will provide keys to attenuating pathogenic autoimmunity. Insofar as the role of Th1 cytokines in IDDM is concerned, interferon gamma is considered a critical player in the etiology, a proinflammatory role has been determined for IDDM, interleukin-2 is considered an "amplification" factor, and tumor necrosis factor-alpha presents dichotomous effects. Regarding the role of Th2 cytokines in IDDM, interleukin-4 is essential for immunoprotection and counterregulation of IDDM, and interleukin-10 plays immunoprotective and destructive roles. Therefore, Th1 and Th2 cytokines, when expressed individually in islets of Langerhans, have provided surprising results in manipulating the IDDM of transgenic NOD mice. The current data show that the same cytokine can produce either protective or pathological effects, depending upon the timing of its participation in the disease process. Of all the cytokines examined, IL-4 seems to be the likely candidate for preventing IDDM.
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PMID:Cytokines and IDDM: implications for etiology and therapy. 1561 24

Understanding of the mechanisms underlying atherosclerotic disorders has evolved beyond the view of a progressive collection of lipids and cellular debris in the vascular wall. Current evidence has implicated inflammatory pathways as an important pathogenic mechanism in atherogenesis and plaque destabilization. Although not necessarily the primary event, inflammation and cytokine activation during plaque formation and destabilization may represent a common final pathway to various stimuli. Thus, it seems that not only 'new' risk factors, such as infections with various microorganisms, but also classic risk factors for cardiovascular disease, such as hyperlipidemia, hypertension and diabetes, may promote their atherogenic effects through inflammatory responses. Indeed, recent reports have suggested that traditional cardiovascular medications may attenuate atherogenesis and enhance plaque stability, at least partly through anti-inflammatory mechanisms. However, uncovering the inflammatory pathways in atherosclerosis has raised the possibility that newer treatment modalities should be more directly targeted against inflammatory mediators. Recently, a series of experimental studies have reported reduction of atherosclerosis by immunomodulatory therapy, such as chemokine blockade, interleukin-10 and immunization/vaccination against oxidized low-density lipoprotein and heat-shock protein. It is conceivable that some of these approaches will be tested clinically and, if successful, they could provide novel treatment strategies in coronary artery disease in humans.
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PMID:Inflammation in coronary artery disease: potential role for immunomodulatory therapy. 1629 1

Targeting of antigens to immature dendritic cells has been shown to result in antigen-specific T-cell tolerance in vivo. In the INS-HA/TCR-HA transgenic mouse model for type 1 diabetes, we tested the potential of the dendritic cell-specific monoclonal antibody DEC-205 conjugated to the hemagglutinin (HA) antigen (DEC-HA) to prevent disease onset. Whereas untreated INS-HA/TCR-HA mice all develop insulitis, and approximately 40% of these mice become diabetic, repeated injection of newborn mice with DEC-HA protected almost all mice from disease development. Histological examination of the pancreata revealed significant reduction of peri-islet infiltrations in DEC-HA-treated mice, and the islet structure remained intact. Moreover, HA-specific CD4+ T-cells from anti-DEC-HA-treated INS-HA/TCR-HA mice exhibited increased expression of Foxp3, cytotoxic T-lymphocyte-associated antigen-4, and the immunosuppressive cytokines interleukin-10 and transforming growth factor-beta. The findings indicate that targeting of the HA antigen to immature dendritic cells in vivo leads to a relative increase of antigen-specific Foxp3+ regulatory T-cells that suppress the development of type 1 diabetes. Our results provide a basis for the development of novel strategies focusing on prevention rather than treatment of autoimmune diseases.
Diabetes 2005 Dec
PMID:On the edge of autoimmunity: T-cell stimulation by steady-state dendritic cells prevents autoimmune diabetes. 1630 54

Autoimmune diabetes in the non-obese diabetic (NOD) mouse is associated with development of inflammation around the islets at around 4-5 weeks of age, which may be prolonged until frank diabetes begins to occur around 12 weeks of age. Although many interventions can halt disease progression if administration coincides with the beginning of the anti-beta cell response, very few are able to prevent diabetes development once insulitis is established. Here we describe a strategy which blocks cellular infiltration of islets and prevents diabetes. Intranasal treatment with the B-subunit of Escherichia coli heat labile enterotoxin (EtxB), a protein that binds GM1 ganglioside (as well as GD1b, asialo-GM1 and lactosylceramide with lower affinities), protected NOD mice from developing diabetes in a receptor-binding dependent manner. Protection was associated with a significant reduction in the number of macrophages, CD4(+) T cells, B cells, major histocompatibility complex class II(+) cells infiltrating the islets. Despite this, treated mice showed increased number of interleukin-10(+) cells in the pancreas, and a decrease in both T helper 1 (Th1) and Th2 cytokine production in the pancreatic lymph node. Disease protection was also transferred with CD4(+) splenocytes from treated mice. Taken together, these results demonstrated that EtxB is a potent immune modulator capable of blocking diabetes.
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PMID:Protection of non-obese diabetic mice from autoimmune diabetes by Escherichia coli heat-labile enterotoxin B subunit. 1642 62


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