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Query: UMLS:C0011854 (type 1 diabetes)
 20,749 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Nonobese diabetic (NOD) mice and some human type 1 diabetes (T1D) patients manifest low to high levels of other autoimmune pathologies. Skewing their cytokine production from a Th1 (primarily IFN-gamma) to a Th2 (primarily IL-4 and IL-10) pattern is a widely proposed approach to dampen the pathogenicity of autoreactive diabetogenic T cells. However, it is important that altered cytokine balances not enhance any other autoimmune proclivities to dangerous levels. Murine CD4 T cells are characterized by a reciprocal relationship between the production of IFN-gamma and expression of the beta-chain component of its receptor (IFN-gamma RB). Thus, NOD mice constitutively expressing a CD2 promoter-driven IFN-gamma RB transgene in all T cells are Th1-deficient. Unexpectedly, NOD.IFN-gamma RB Tg mice were found to develop a lethal early paralytic syndrome induced by a CD8 T cell-dependent autoimmune-mediated myositis. Furthermore, pancreatic insulitis levels were not diminished in 9-wk-old NOD.IFN-gamma RB Tg females, and overt T1D developed in the few that survived to an older age. Autoimmune-mediated myositis is only occasionally detected in standard NOD mice. Hence, some manipulations diminishing Th1 responses can bring to the forefront what are normally secondary autoimmune pathologies in NOD mice, while also failing to dependably abrogate pancreatic beta cell destruction. This should raise a cautionary note when considering the use of protocols that induce alterations in cytokine balances as a means of blocking progression to overt T1D in at-risk humans.
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PMID:Paralytic autoimmune myositis develops in nonobese diabetic mice made Th1 cytokine-deficient by expression of an IFN-gamma receptor beta-chain transgene. 1259 5

Nonobese diabetic (NOD) mice expressing the BDC2.5 TCR transgene are useful for studying type 1 diabetes. Several peptides have been identified that are highly active in stimulating BDC2.5 T cells. Herein, we describe the use of I-Ag7 tetramers containing two such peptides, p79 and p17, to detect and characterize peptide-specific T cells. The tetramers could stain CD4(+) T cells in the islets and spleens of BDC2.5 transgenic mice. The percentage of CD4(+), tetramer(+) T cells increased in older mice, and it was generally higher in the islets than in the spleens. Our results also showed that tetAg7/p79 could stain a small population of CD4(+) T cells in both islets and spleens of NOD mice. The percentage of CD4(+), tetramer(+) T cells increased in cells that underwent further cell division after being activated by peptides. The avidity of TCRs on purified tetAg7/p79(+) T cells for tetAg7/p79 was slightly lower than that of BDC2.5 T cells. Although tetAg7/p79(+) T cells, like BDC2.5 T cells, secreted a large quantity of IFN-gamma, they were biased toward being IL-10-producing cells. Additionally, <3% of these cells expressed TCR Vbeta4. In vivo adoptive transfer experiments showed that NOD/scid recipient mice cotransferred with tetAg7/p79(+) T cells and NOD spleen cells, like mice transferred with NOD spleen cells only, developed diabetes. Therefore, we have generated Ag-specific tetramers that could detect a heterogeneous population of T cells, and a very small number of NOD mouse T cells may represent BDC2.5-like cells.
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PMID:Detection and characterization of T cells specific for BDC2.5 T cell-stimulating peptides. 1268 29

Dietary antigens are candidate environmental factors in the pathogenesis of type 1 diabetes. In the non-obese diabetic (NOD) mouse, an animal model of type 1 diabetes, cereal-based diets promote disease development, whereas the diets based on hydrolysed proteins or non-diabetogenic proteins are protective. The hypothesis that diabetogenic diets modulate the cytokine balance in the gut was tested. NOD mice were fed with NTP-2000 (mainly a wheat-based milk-free diet) or Prosobee (a semi-purified hypoallergenic diet based on soy protein isolate) or Prosobee plus casein (milk protein fraction). The mRNA levels of IFN-gamma, IL-10, TNF-alpha, TGF-beta, and inducible NO synthase in the small intestine and the Peyer's patches were determined by semi-quantitative RT-PCR. Mice fed on the cereal-based NTP-2000 diet expressed higher levels of the Th1-type and pro-inflammatory markers IFN-gamma, TNF-alpha, and inducible NO synthase mRNA compared to the Prosobee-fed animals. The expression of the counterregulatory cytokines IL-10 and TGF-beta was unaffected. This resulted in a significant bias of the intestinal cytokine balance towards T helper cell type 1 after feeding NTP-2000. The cytokine mRNA levels in the gut-associated Peyer's patches were not affected. Thus, modulation of gut immunoreactivity by diet may contribute to disease development in NOD mice.
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PMID:A wheat-based, diabetes-promoting diet induces a Th1-type cytokine bias in the gut of NOD mice. 1269 53

Theiler murine encephalomyelitis virus-induced demyelinating disease (TMEV-IDD) is a mouse model of chronic-progressive multiple sclerosis (MS) characterized by Th1-mediated CNS demyelination and spastic hindlimb paralysis. Existing MS therapies reduce relapse rates in 30% of relapsing-remitting MS patients, but are ineffective in chronic-progressive disease, and their effects on disability progression are unclear. Experimental studies demonstrate cannabinoids are useful for symptomatic treatment of spasticity and tremor in chronic-relapsing experimental autoimmune encephalomyelitis. Cannabinoids, however, have reported immunosuppressive properties. We show that the cannabinoid receptor agonist, R+WIN55,212, ameliorates progression of clinical disease symptoms in mice with preexisting TMEV-IDD. Amelioration of clinical disease is associated with downregulation of both virus and myelin epitope-specific Th1 effector functions (delayed-type hypersensitivity and IFN-gamma production) and the inhibition of CNS mRNA expression coding for the proinflammatory cytokines, TNF-alpha, IL1-beta, and IL-6. Clinical trials investigating the therapeutic potential of cannabinoids for the symptomatic treatment of MS are ongoing, and this study demonstrates that they may also have potent immunoregulatory properties.
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PMID:Immunoregulation of a viral model of multiple sclerosis using the synthetic cannabinoid R+WIN55,212. 1269 42

Recent studies incriminating tumor necrosis factor (TNF)-alpha as the final effector in pancreatic beta-cell death in type 1 diabetes underscore the potential role of TNF-alpha-dependent NF-kappaB activation as an important modulator of pancreatic beta-cell death in autoimmune diabetes. Although nuclear factor (NF)-kappaB activation has been implicated in the protection of target cells against apoptosis by a variety of death effectors, its role in pancreatic islet cell death is not clear. We studied the role of NF-kappaB activation in pancreatic islet cell death by using a gamma-interferon (IFN-gamma)/TNF-alpha synergism model we had previously reported. TNF-alpha induced inhibitor of kappaB (IkappaB) degradation and p65 translocation from cytoplasm to nuclei in MIN6N8 insulinoma cells. The NF-kappaB DNA-binding nuclear complex activated by TNF-alpha contained both the p65 and p50 subunit. IFN-gamma pretreatment did not affect TNF-alpha-induced NF-kappaB activation. Treatment with a proteasome inhibitor blocked p65 translocation and induced susceptibility to TNF-alpha in otherwise resistant insulinoma cells or primary pancreatic islet cells. Specific inhibition of NF-kappaB activation by adenoviral transduction of IkappaB "superrepressor" also sensitized insulinoma cells and primary islet beta-cells to TNF-alpha-induced apoptosis. These results suggest the protective role of NF-kappaB activation against cytokine-mediated pancreatic beta-cell death, contrary to previous reports implicating NF-kappaB as a mediator of pancreatic islet cell death.
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PMID:Nuclear factor kappaB protects pancreatic beta-cells from tumor necrosis factor-alpha-mediated apoptosis. 1271 48

We have been investigating the potential utility of engineered cell lines as surrogates for primary islet cells in treatment of type 1 diabetes. To this end, two strategies that have emerged for procuring cell lines with resistance to immune-mediated damage are 1) selection of cytokine-resistant cell lines by growth of INS-1 insulinoma cells in iteratively increasing concentrations of interleukin (IL)-1beta + gamma-interferon (IFN-gamma), and 2) stable overexpression of the anti-apoptotic gene bcl-2 in INS-1 cells. Herein, we show that bcl-2-overexpressing cells are resistant to the cytotoxic effects of reactive oxygen and nitrogen species (ROS/RNS), but are only modestly protected against high concentrations of IL-1beta + INF-gamma, whereas the converse is true in cytokine selected cells. We also found that the combination of bcl-2 expression and cytokine selection confers a broader spectrum of resistance than either procedure alone, such that the resultant cells are highly resistant to cytokines and ROS/RNS, with no impairment in glucose-stimulated insulin secretion. INS-1-derived cells with combined bcl-2 expression and cytokine selection are also more resistant to damage induced by coculture with mitogen-activated peripheral blood mononuclear cells. Surprisingly, application of the cytokine selection procedure to bcl-2-overexpressing cells does not result in impairment of nuclear factor-kappaB translocation, iNOS expression, and NO production, as clearly occurs upon application of the selection procedure to cells without bcl-2 overexpression. Further investigation of the diverse pathways involved in the development of cytokine and ROS/RNS resistance may define simplified and specific strategies for preservation of beta-cell mass.
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PMID:Discrete and complementary mechanisms of protection of beta-cells against cytokine-induced and oxidative damage achieved by bcl-2 overexpression and a cytokine selection strategy. 1276 53

Advanced glycation end products (AGEs) are implicated in beta-cell oxidant stress. Diet-derived AGE (dAGE) are shown to contribute to end-organ toxicity attributed to diabetes. To assess the role of dAGE on type 1 diabetes, NOD mice were exposed to a high-AGE diet (H-AGE) and to a nutritionally similar diet with approximate fivefold-lower levels of N(epsilon)-carboxymethyllysine (CML) and methylglyoxal-derivatives (MG) (L-AGE). Suppression of serum CML and MG in L-AGE-fed mice was marked by suppression of diabetes (H-AGE mice >94% vs. L-AGE mice 33% in founder [F](0), 14% in F(1), and 13% in F(2) offspring, P < 0.006) and by a delay in disease onset (4-month lag). Survival for L-AGE mice was 76 vs. 0% after 44 weeks of H-AGE mice. Reduced insulitis in L-AGE versus H-AGE mice (P < 0.01) was marked by GAD- and insulin-unresponsive pancreatic interleukin (IL)-4-positive CD4+ cells compared with the GAD- and insulin-responsive interferon (IFN)-gamma-positive T-cells from H-AGE mice (P < 0.005). Splenocytes from L-AGE mice consisted of GAD- and insulin-responsive IL-10-positive CD4+ cells compared with the IFN-gamma-positive T-cells from H-AGE mice (P < 0.005). Therefore, high AGE intake may provide excess antigenic stimulus for T-cell-mediated diabetes or direct beta-cell injury in NOD mice; both processes are ameliorated by maternal or neonatal exposure to L-AGE nutrition.
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PMID:Fetal or neonatal low-glycotoxin environment prevents autoimmune diabetes in NOD mice. 1276 55

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

It has been suggested that class I and class II MHC are contributing factors for numerous diseases including autoimmune thyroid diseases, type 1 diabetes, rheumatoid arthritis, Alzheimer's disease, and multiple sclerosis. The class II trans-activator (CIITA), which is a non-DNA-binding regulator of class II MHC transcription, regulates the constitutive and inducible expression of the class I and class II genes. FRTL-5 thyroid cells incubated in the presence of IFN-gamma have a significantly higher level of cell surface rat MHC class II RTI.B. However, the IFN-gamma-induced RT1.B expression was suppressed significantly in cells incubated in the presence of thyrotropin. Thyrotropin (TSH) represses IFN-gamma-induced CIITA expression by inhibiting type IV CIITA promoter activity through the suppression of STAT1 activation and IFN regulatory factor 1 induction. This study found that TSH induces transcriptional activation of the STAT3 gene through the phosphorylation of STAT3 and CREB activation. TSH induces SOCS-1 and SOCS-3, and TSH-mediated SOCS-3 induction was dependent on STAT3. The cell line stably expressing the wild-type STAT3 showed a higher CIITA induction in response to IFN-gamma and also exhibited TSH repression of the IFN-gamma-mediated induction of CIITA. However, TSH repression of the IFN-gamma-induced CIITA expression was not observed in FRTL-5 thyroid cells, which stably expresses the dominant negative forms of STAT3, STAT3-Y705F, and STAT3-S727A. This report suggests that TSH is also engaged in immunomodulation through signal cross-talk with the cytokines in thyroid cells.
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PMID:Thyrotropin-mediated repression of class II trans-activator expression in thyroid cells: involvement of STAT3 and suppressor of cytokine signaling. 1284 26

The present study was undertaken to analyze the regulatory T cells generated in response to class I derived self-I-A beta(g7) (54-76) peptide. It was observed T cells from young unprimed type 1 diabetes (T1D) prone NOD mice did not respond to self-I-A beta(g7) (54-76) peptide although T cells from primed young NOD mice showed a strong response. T cells from young unprimed BALB/c mice responded to self-I-A beta(d) (62-78) peptide. However, a breakdown of tolerance to these peptides was observed with age in both the strains. Culture supernatant from I-A beta(g7) (54-76) peptide-primed cells secreted large amounts of TGF-beta and inhibited T cell responses in allogeneic-MLR. Further, I-A beta(g7) (54-76) peptide specific T cell lines from young (I-A.Y) and diabetic (I-A.D) NOD mice were established. I-A.Y secreted IL-4, TGF-beta and IL-10 while I-A.D T cell line secreted IL-10 and IFN-gamma. We found that I-A.D T cell line induced diabetes when transferred in NOD/SCID mice but I-A.Y T cell line did not induce disease. These results show that immunization of NOD mice with I-A beta(g7) (54-76) peptide at a younger age induces a regulatory T cell response suggesting that correcting the defects in immunoregulatory mechanisms using self-MHC peptides may be one of the approaches to prevent autoimmune diseases like T1D.
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PMID:Regulation of type 1 diabetes by a self-MHC class II peptide: role of transforming growth factor beta (TGF-beta). 1288 99


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