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)

Dimeric Fc receptor (FcR) nonbinding anti-CD3 antibodies have been developed to minimize toxicities associated with classical anti-CD3 monoclonal antibodies (e.g., OKT3). Studies with murine analogs of non-FcR-binding antibodies have shown reduced mitogenicity compared to OKT3. In a trial of an FcR nonbinding humanized anti-CD3 mAb hOKT3gamma1(Ala-Ala) for treatment of patients with type 1 diabetes, we found significant increases in IL-10 and IL-5 in the serum of 63% and 72% of patients, respectively, and TNF-alpha and IL-6 levels that were lower than those previously reported following OKT3 therapy. The activation signal delivered by hOKT3gamma1(Ala-Ala) was associated with calcium signaling and cytokine production by previously activated human cells in vitro. However, the production of IL-10, compared to IFN-gamma on a molar basis, was greater after culture with hOKT3gamma1(Ala-Ala) than with OKT3. Flow cytometric studies confirmed that OKT3 induced IFN-gamma and IL-10 production, but hOKT3gamma1(Ala-Ala) induced only detectable IL-10 production in CD45RO(+) cells. Moreover, in vivo, we found IL-10(+)CD4(+) T cells after drug treatment. These cells were heterogeneous but generally CD45RO(+), CTLA-4(-), and expressed CCR4. A subgroup of these cells expressed TGF-beta. Thus, the non-FcR binding anti-CD3 mAb, hOKT3gamma1(Ala-Ala) delivers an activation signal to T cells that is quantitatively and qualitatively different from OKT3. It leads to the generation of T cells that might inhibit the autoimmune response and may be involved in the beneficial effect on beta cell destruction in Type 1 diabetes.
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PMID:Activation of human T cells by FcR nonbinding anti-CD3 mAb, hOKT3gamma1(Ala-Ala). 1256 67

Type 1 diabetes is characterized by a chronic inflammatory response resulting in the selective destruction of the insulin-producing beta cells. We have previously demonstrated that dendritic cells (DCs) prepared from nonobese diabetic (NOD) mice, a model for spontaneous type 1 diabetes, exhibit hyperactivation of NF-kappaB resulting in an increased capacity to secrete proinflammatory cytokines and stimulate T cells compared with DCs of nondiabetic strains of mice. In the current study, the activational status of NF-kappaB and its role in regulating the APC function of macrophages (Mphi) prepared from NOD, nonobese resistant (NOR), and BALB/c mice was investigated. Independent of the stimulus, splenic and bone marrow-derived Mphi prepared from NOD mice exhibited increased NF-kappaB activation relative to NOR and BALB/c Mphi. This hyperactivation was detected for different NF-kappaB complexes and correlated with increased IkappaBalpha degradation. Furthermore, increased NF-kappaB activation resulted in an enhanced capacity of NOD vs NOR or BALB/c Mphi to secrete IL-12(p70), TNF-alpha, and IL-1alpha, which was inhibited upon infection with an adenoviral recombinant encoding a modified form of IkappaBalpha. In contrast, elevated NF-kappaB activation had no significant effect on the capacity of NOD Mphi to stimulate CD4(+) or CD8(+) T cells in an Ag-specific manner. These results demonstrate that in addition to NOD DCs, NOD Mphi exhibit hyperactivation of NF-kappaB, which correlates with an increased ability to mediate a proinflammatory response. Furthermore, NF-kappaB influences Mphi APC function by regulating cytokine secretion but not T cell stimulation.
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PMID:NF-kappa B hyperactivation has differential effects on the APC function of nonobese diabetic mouse macrophages. 1257 41

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

Transplantation of islets is becoming an established method for treating type 1 diabetes. However, viability of islets is greatly affected by necrosis/apoptosis induced by oxidative stress and other insults during isolation and subsequent in vitro culture. Expression of cytoprotective proteins, such as heme oxygenase-1 (HO-1), reduces the deleterious effects of oxidative stress in transplantable islets. We have generated a fusion protein composed of HO-1 and TAT protein transduction domain (TAT/PTD), an 11-aa cell penetrating peptide from the human immunodeficiency virus TAT protein. Transduction of TAT/PTD-HO-1 to insulin-producing cells protects against TNF-alpha-mediated cytotoxicity. TAT/PTD-HO-1 transduction to islets does not impair islet physiology, as assessed by reversion of chemically induced diabetes in immunodeficient mice. Finally, we report that transduction of HO-1 fusion protein into islets improves islet viability in culture. This approach might have a positive impact on the availability of islets for transplantation.
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PMID:Heme oxygenase-1 fused to a TAT peptide transduces and protects pancreatic beta-cells. 1276 12

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is expressed in different tissues and cells, including pancreas and lymphocytes, and can induce apoptosis in various tumor cells but not in most normal cells. The specific roles of TRAIL in health and disease remain unclear. Here we show by cDNA array analyses that TRAIL gene expression is upregulated in pancreatic islets during the development of autoimmune type 1 diabetes in nonobese diabetic (NOD) mice and in Min6 islet beta-cells activated by TNF-alpha + interferon-gamma. However, stimulation of freshly isolated pancreatic islets or Min6 cells with TRAIL did not induce their apoptosis. TRAIL blockade exacerbates the onset of type 1 diabetes in NOD.Scid recipients of transferred diabetogenic T-cells and in cyclophosphamide-treated NOD mice. TRAIL inhibits the proliferation of NOD diabetogenic T-cells by suppressing interleukin (IL)-2 production and cell cycle progression, and this inhibition can be rescued in the presence of exogenous IL-2. cDNA array and Western blot analyses indicate that TRAIL upregulates the expression of the cdk inhibitor p27(kip1). Our data suggest that TRAIL is an important immune regulator of the development of type 1 diabetes.
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PMID:Blockade of tumor necrosis factor-related apoptosis-inducing ligand exacerbates type 1 diabetes in NOD mice. 1288 12

Theiler's murine encephalomyelitis virus-induced demyelinating disease (TMEV-IDD) is a well-characterized murine model of the chronic-progressive form of human multiple sclerosis (MS) characterized by the activation of myelin-specific autoreactive CD4 Th1 cells via epitope spreading. To gain an understanding of the potential role of central nervous system (CNS)-resident cells in the presentation of endogenous myelin epitopes, we determined the individual antigen presentation and effector potential of resident microglia vs. infiltrating macrophages in the CNS of mice with ongoing TMEV-IDD by performing functional analysis of these populations separated to high purity by flow cytometric sorting based on their level of CD45 expression. Unlike microglia from nai;ve mice, peptide-pulsed CD45(lo) microglia isolated at the onset of clinical disease were as efficient as CNS-infiltrating CD45(hi) macrophages in activating proliferation and IFN-gamma production by myelin-peptide specific Th1 cells. In contrast, during the chronic stages of TMEV-IDD, CNS-infiltrating macrophages were more highly activated than the resident microglia as reflected both by higher expression of cell surface molecules associated with APC function and enhanced functional ability of spinal cord-infiltrating macrophages to stimulate T cell proliferation in vitro. Interestingly, both microglia and infiltrating macrophages expressed similar profiles of effector molecules such as IL-1, IL-6, IL-12 p40, TNF-alpha, and iNOS. Collectively, this is the first report comparing the antigen-presenting phenotype and function of microglia and infiltrating macrophages in a virus-induced model of CNS demyelination demonstrating that the resident microglia are capable APCs and may play an important role in antigen presentation at the onset of clinical disease and contribute to effector myelin destruction.
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PMID:Microglia are activated to become competent antigen presenting and effector cells in the inflammatory environment of the Theiler's virus model of multiple sclerosis. 1459

NOD mice have a relative deficiency of CD4+CD25+ regulatory T cells that could result in an inability to maintain peripheral tolerance. The aim of this study was to induce the generation of CD4+CD25+ regulatory T cells in response to autoantigens to prevent type 1 diabetes (T1D). We found that immunization of NOD mice with insulin B-chain peptide B:9-23 followed by 72 h in vitro culture with B:9-23 peptide induces generation of CD4+CD25+ regulatory T cells. Route of immunization has a critical role in the generation of these cells. Non-autoimmune mice BALB/c, C57BL/6 and NOR did not show up regulation of CD4+CD25+ regulatory T cells. These cells secreted large amounts of TGF-beta and TNF-alpha with little or no IFN-gamma and IL-10. Adoptive transfer of these CD4+CD25+ regulatory T cells into NOD-SCID mice completely prevented the adoptive transfer of disease by diabetogenic T cells. Although, non-self antigenic OVA (323-339) peptide immunization and in vitro culture with OVA (323-339) peptide does result in up regulation of CD4+CD25+ T cells, these cells did not prevent transfer of diabetes. Our study for the first time identified the generation of antigen-specific CD4+CD25+ regulatory T cells specifically in response to immunization with B:9-23 peptide in NOD mice that are capable of blocking adoptive transfer of diabetes. Our results suggest the possibility of using autoantigens to induce antigen-specific regulatory T cells to prevent and regulate autoimmune diabetes.
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PMID:CD4+CD25+ regulatory T cells generated in response to insulin B:9-23 peptide prevent adoptive transfer of diabetes by diabetogenic T cells. 1459 47

Several studies have demonstrated that diabetes is a risk factor for developing periodontal disease, increasing its prevalence and severity. Furthermore, periodontitis may impair the metabolic control and adequate treatment of diabetic patients. LPS from Gram-negative bacteria penetrates the periodontal tissues and subsequently recruits and activates immune cells. Progression to severe periodontitis with loss of supporting structures is mediated by several factors, including secretion of a broad spectrum of inflammatory and destructive (PGE2). mediators such as cytokines (TNF-alpha, IL-1b and IL-6), chemokines (IL-8) and prostaglandin E2. The aim of this work is to investigate differences in the TNF-a, IL-1b and IL-6 expression and prostaglandin E2 (PGE2) release in blood from diabetic patients with and without aggressive periodontitis (AP) stimulated with lipopolysaccharide (LPS). For this purpose we recruited 29 Type 1 diabetes mellitus (DM) patients, 14 with AP and 15 without AP. Fourteen healthy individuals formed the control group. For cytokine expression and PGE2 secretion, an ex vivo whole blood culture system was used. Cytokines and PGE2 were detected by commercial immunometric assays. A wide range of inter-individual variability in spontaneous and LPS-induced TNF-alpha, IL-1b and IL-6 levels in patient groups and controls was found. The mean of spontaneous and LPS-induced TNF-alpha and IL-1b levels did not differ significantly (p > 0.5) when patients were compared to control individuals. Although not significant, the spontaneous TNF-alpha, IL-1b and IL-6 levels in the group of Type 1 DM with AP were higher than in controls, while in diabetic patients without AP, these values were depressed in comparison with controls. In both groups of patients, the means of LPS-induced IL-6 levels were higher than the controls but the differences observed were not significant (p = 0.07). However, the LPS-induced PGE2 levels varied significantly when all groups were compared (p = 0.007). The means of LPS-induced PGE2 levels for Type 1 diabetic patients with AP (p = 0.0009) and without AP (p = 0.024) were significantly higher than the levels observed for healthy controls. Finally, we conclude that Type 1 diabetic patients with or without AP did not express higher LPS-induced TNF-a, IL-1b and IL-6 levels than controls. However, the PGE2 levels released were significantly higher than those detected in controls.
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PMID:Ex vivo lipopolysaccharide (LPS)-induced TNF-alpha, IL-1beta, IL-6 and PGE2 secretion in whole blood from Type 1 diabetes mellitus patients with or without aggressive periodontitis. 1465 85


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