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)

To study the relative roles of CD4(+)and CD8(+)T cells and their cytokine products in autoimmune diabetes development, we selectively depleted CD4(+)and CD8(+)T cells in autoimmune diabetes-prone (DP) biobreeding (BB) rats, by administrations of anti-CD2 and anti-CD8 monoclonal antibody (mAb) respectively. We then analysed cytokine mRNA expression, by PCR assay, in mononuclear leukocytes isolated from islets and spleens of control and mAb-treated DP-BB rats. Depletion of CD4(+)T cells (by anti-CD2 mAb) in blood, spleen and islets prevented diabetes development in DP-BB rats, and depletion of CD8(+)T cells (by anti-CD8 mAb) delayed and significantly decreased diabetes incidence. Depletion of either CD4(+)or CD8(+)T cells completely prevented IFN-gamma mRNA upregulation in islets of DP-BB rats above the low level expressed in islets of diabetes-resistant (DR) BB rats. Also, IL-10 mRNA levels in islets of DP-BB rats were significantly decreased by depletion of either CD4(+)or CD8(+)T cells, whereas the effects of the anti-T cell mAb on mRNA levels of other cytokines in islets (IL-2, IL-4, IL-12p40, and TNF-alpha) were discordant. In contrast, both mAb treatments significantly upregulated IL-4 and TNF-alpha mRNA levels in spleens of DP-BB rats. These results demonstrate that islet infiltration by both CD4(+)and CD8(+)T cells is required for IFN-gamma and IL-10 production in islets and beta-cell destruction. Depletion of either CD4(+)or CD8(+)T cells may prevent beta-cell destruction by decreasing IFN-gamma and IL-10 production in islets and increasing IL-4 and TNF-alpha production systemically.
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PMID:Both CD4(+)and CD8(+)T cells are required for IFN-gamma gene expression in pancreatic islets and autoimmune diabetes development in biobreeding rats. 1004 31

It is not clear if a Th1/Th2 imbalance in Type 1 diabetes (insulin-dependent diabetes mellitus, IDDM) would lead to a particular antigen-specific IgG subclass dominant as had been shown in the mouse model. In new-onset Type 1 diabetics, an autoantibody response to glutamate decarboxylase (GADab) is frequently observed but the GADab subclass repertoire is not well-established. We determined the systemic levels of representative Th1 and Th2 cytokines and the GADab IgG subclass distribution in 41 Chinese IDDM patients of whom 26 were recently diagnosed (< or = 1 year) and 32 had GADab, to ascertain a likely association of antigen-specific antibody isotype and the Th1/Th2 dichotomy. With high-sensitivity ELISA systems that measure sub-picogram cytokine concentrations, 26 of the 41 patients (63.4%) had at least one of the pro-inflammatory Th1 cytokines (TNF-alpha, IFN-gamma and IL-12) detected. Fewer patients (4/41) had the anti-inflammatory Th2 cytokine IL-4 detected. For IL-10, all subjects had measurable quantities but only three diabetics had levels above the upper limit for healthy subjects (n = 20). Grouped according to the profile of detectable cytokines, there were 24 Th1, 2 Th2 and 2 Th0 patterns. GAD-specific IgG1 antibody was more frequently expressed; 22 of 32 GADab[+] patients. The rank order for the GADab subclasses was IgG1 > 4 > 3 > 2; IgG2 was found in 11 GADab[+] patients. Recent-onset diabetics have a similar ranking of the GAD-specific IgG subclasses. In human Type 1 diabetes, a predominance of GAD-specific IgG1 antibody response is observed together with a dominant Th1 cytokine pattern.
Diabetes Res Clin Pract 1999 Feb
PMID:Systemic levels of cytokines and GAD-specific autoantibodies isotypes in Chinese IDDM patients. 1022 65

Expression of IL-10 transgene (tg) in pancreatic beta cells failed to induce autoimmune insulitis and diabetes in (BALB/c x NOD)F1 mice. However, IL-10-expressing tg littermates from backcrosses (N2 and N3) with NOD mice became diabetic at 5 to 10 weeks of age in an MHC-dependent manner. In this study, we tested the possibility that enhancement in frequency of islet antigen (Ag)-specific T cells overrides the protective effects of a diabetes-resistant genetic background and promotes diabetes in IL-10 tg (BALB/c x NOD)F1 mice. For this test, we introduced the IL-10 transgene into tg BDC2.5 mice expressing the islet Ag-specific Vbeta4 T cell repertoire by breeding Ins-IL-10+/BALB/c mice with BDC2.5 mice. The progeny (Ins-IL-10+/BALB/c x BDC2.5+)F1 mice doubly tg for IL-10 and Vbeta4 (BDC2.5) T cell repertoire, developed diabetes at 10 to 18 weeks of age with a much more aggressive T cell infiltrate in the pancreatic islets than in single tg mice. Surprisingly, these diabetic mice were free from acute pancreatitis but had apoptotic beta cells in the islet infiltrate. Conversely, mice tg for Vbeta4 (BDC2.5) T cell repertoire but not IL-10 had no diabetes and no apoptotic beta cells in the islet infiltrate. Therefore, an increase in the frequency of islet-specific T cells apparently overcomes the protection from diabetes by a resistant genetic background. Interestingly, N2 backcross mice doubly tg for Vbeta4 (BDC2.5) T cell repertoire and IL-10, compared to N2 backcross mice tg for IL-10 only, eventually became diabetic but with a delayed onset and reduced incidence of disease. These findings demonstrate that, along with IL-10, an increase in frequency of islet antigen-specific T cells (a) overrides the protective effect of genetic resistance to autoimmune diabetes in F1 mice and (b) delays the onset of an otherwise accelerated diabetes in (Ins-IL-10+/NOD)N2 backcross mice.
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PMID:Differential impact of T cell repertoire diversity in diabetes-prone or -resistant IL-10 transgenic mice. 1022 59

Non-obese diabetic (NOD) mice spontaneously develop diabetes. Ourselves and others have previously shown that oral and nasal administration of insulin or glutamic acid decarboxylase (GAD) suppresses development of diabetes in the NOD mouse and that this suppression appears secondary to the generation of regulatory T cells that act by secreting anti-inflammatory cytokines such as IL-4 and TGF-beta. In the present study, we analysed cytokine patterns associated with mucosal administration of insulin B-chain, B-chain peptide 10-24 and GAD peptide 524-543 and derived lines and clones from mucosally-treated animals. Mice were fed five times (400-600 microg/feed) or nasally-treated three times (60 microg/application), and 2 days after the last treatment were immunized in the footpad with the mucosally administered antigen in CFA. Primary immune responses in the popliteal lymph node were measured 10 days after immunization and lines and clones were then established from the primary cultures. There was significantly less IFN-gamma production in mucosally-treated mice associated with increased production of IL-10 and TGF-beta. The nature of the antigen appeared to determine cytokine production as the B-chain given either orally or nasally primed for TGF-beta responses, whereas mucosally administered B-chain peptide 10-24 primed for IL-10. T cell clones, established from draining lymph nodes of fed or nasally-treated animals, secreted IL-4, IL-10 and TGF-beta whereas those from non-fed mice secreted IL-2 and IFN-gamma. Transfer of Th1 lines with splenocytes from diabetic NOD mice into NOD or NOD/SCID animals accelerated diabetes, whereas transfer of Th2 lines suppressed the development of diabetes. Our results further support a role for Th2-type cells in the regulation of diabetes in NOD mice.
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PMID:Regulatory Th2-type T cell lines against insulin and GAD peptides derived from orally- and nasally-treated NOD mice suppress diabetes. 1033 Feb 96

GAD65 (glutamic acid decarboxylase) is an important autoantigen in both type 1 (insulin-dependent) diabetes mellitus (IDDM) and the neurological autoimmune disease stiff-man syndrome (SMS), and is expressed in pancreatic islets as well as the nervous system. Still, only 30% of SMS patients also have type 1 diabetes. To study regulation of T cell responsiveness to GAD65, we investigated a non-diabetic SMS patient with HLA-DR3/7 (predisposing to type 1 diabetes) and high levels of type 1 diabetes-associated autoantibodies against GAD65 and islet cells, and compared the results with those of her diabetic son and two other SMS patients. T cell responses to GAD65 were repeatedly absent in primary stimulation, whereas IA-2, islet antigen and tetanus toxoid induced significant T cell proliferation. However, after in vitro restimulation, GAD65 reactive T cell lines and clones were obtained that were HLA-DR3 restricted, and cross-reactive with a homogenate of purified human pancreatic islets. These T cells produced the immunoregulatory cytokine IL-10 in combination with IFN-gamma and IL-4 (Th0). The dominant T cell epitope was mapped to the central region of GAD65. Although no primary response to whole GAD65 was detectable, the naturally processed GAD65 peptide epitope was recognized vigorously in the primary stimulation assay. The lack of detectable primary T cell responses to GAD65, together with the GAD65-specific cytokine production of restimulated T cells, suggest that GAD65-specific cellular autoimmunity in this patient is suppressed and may be related to the absence of diabetes despite humoral autoreactivity and genetic predisposition.
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PMID:GAD65-Reactive T cells in a non-diabetic stiff-man syndrome patient. 1033 Mar

Multiple sclerosis (MS) is a T cell-dependent chronic inflammatory disease of the central nervous system. The role of chemokines in MS and its different stages is uncertain. Recent data suggest a bias in expression of chemokine receptors by Th1 vs. Th2 cells; human Th1 clones express CXCR3 and CCR5 and Th2 clones express CCR3 and CCR4. Chemokine receptors expressed by Th1 cells may be important in MS, as increased interferon-gamma (IFN-gamma) precedes clinical attacks, and IFN-gamma injection induces disease exacerbations. We found CXCR3(+) T cells increased in blood of relapsing-remitting MS, and both CCR5(+) and CXCR3(+) T cells increased in progressive MS compared with controls. Furthermore, peripheral blood CCR5(+) T cells secreted high levels of IFN-gamma. In the brain, the CCR5 ligand, MIP-1alpha, was strongly associated with microglia/macrophages, and the CXCR3 ligand, IP-10, was expressed by astrocytes in MS lesions but not unaffected white matter of control or MS subjects. Areas of plaque formation were infiltrated by CCR5-expressing and, to a lesser extent, CXCR3-expressing cells; Interleukin (IL)-18 and IFN-gamma were expressed in demyelinating lesions. No leukocyte expression of CCR3, CCR4, or six other chemokines, or anti-inflammatory cytokines IL-5, IL-10, IL-13, and transforming growth factor-beta was observed. Thus, chemokine receptor expression may be used for immunologic staging of MS and potentially for other chronic autoimmune/inflammatory processes such as rheumatoid arthritis, autoimmune diabetes, or chronic transplant rejection. Furthermore, these results provide a rationale for the use of agents that block CCR5 and/or CXCR3 as a therapeutic approach in the treatment of MS.
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PMID:CCR5(+) and CXCR3(+) T cells are increased in multiple sclerosis and their ligands MIP-1alpha and IP-10 are expressed in demyelinating brain lesions. 1035 6

The impact of exposure to lead on gut cytokine gene expression and oral tolerance was analyzed. Oral tolerization with ovalbumin (OVA) increased levels of IL-10 and TGF-beta in gut tissue while IFN-gamma mRNA levels remained unchanged in both autoimmune diabetes prone NOD and normal C57BL/6 mice. This shift towards Th2/Th3 type cytokine gene expression was completely abolished by concomitant treatment with PbCl2 (6 x 0.5 mg/kg) in NOD mice while the cytokine balance in C57BL/6 mice was unaffected. Suppression of Th2/Th3 type cytokine expression was associated with a dampened oral tolerance response to OVA as determined by T cell proliferation assays. We conclude that in autoimmunity prone NOD mice environmental toxicants may disturb immune homeostasis by targeting the gut immune system.
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PMID:The gut cytokine balance as a target of lead toxicity. 1037 10

Antigenic proliferative responses of peripheral blood mononuclear cells (PBMC) to insulin were studied in 44 type 1 new-onset diabetic subjects. Of them, 14 (32%) had a stimulation index (> or =3) above the mean + 3 SD of 39 healthy controls and of 7 of 15 (47%) diabetic patients of long duration (P = 0.001). Responses to insulin were not dictated by specific major histocompatibility complex class II association and were not observed in normal subjects with diabetes-associated human leukocyte antigen-DR/DQ alleles. Whereas no relation of PBMC reactivity with insulin autoantibodies was found, there was a positive correlation with the presence of at least one of the four autoantibodies tested and with IA-2 antibody. An interesting finding was that the proportion of patients with subsequent low insulin requirement, up to 24 months, was significantly higher in patients who showed PBMC reactivity to insulin (8 of 8) than in those who did not (10 of 24, 42%; P = 0.004). The former had a higher mean stimulation index than the latter (3.3+/-2.6 vs. 1.5+/-0.6; P = 0.006). Furthermore, interleukin-4 (IL-4) production was lower in type 1 diabetic patients who proliferated to insulin than in those who did not (23+/-15 vs. 64+/-47 pg/mL; P = 0.04), but interferon-gamma, IL-2, and IL-10 productions were similar. In conclusion, these results suggest that proliferation to insulin may reflect the presence of an higher residual beta-cell mass.
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PMID:The relationship between peripheral T cell reactivity to insulin, clinical remissions and cytokine production in type 1 (insulin-dependent) diabetes mellitus. 1040 14

The development of type 1 diabetes in animal models is T cell and macrophage dependent. Islet inflammation begins as peripheral benign Th2 type insulitis and progresses to destructive Th1 type insulitis, which is driven by the innate immune system via secretion of IL-12 and IL-18. We now report that daily application of IL-18 to diabetes-prone female nonobese diabetic mice, starting at 10 wk of age, suppresses diabetes development (p < 0.001, 65% in sham-treated animals vs 33% in IL-18-treated animals by 140 days of age). In IL-18-treated animals, we detected significantly lower intraislet infiltration (p < 0.05) and concomitantly an impaired progression from Th2 insulitis to Th1-dependent insulitis, as evidenced from IFN-gamma and IL-10 mRNA levels in tissue. The deficient progression was probably due to lesser mRNA expression of the Th1 driving cytokines IL-12 and IL-18 by the innate immune system (p < 0.05). Furthermore, the mRNA expression of inducible NO synthase, a marker of destructive insulitis, was also not up-regulated in the IL-18-treated group. IL-18 did not exert its effect at the levels of islet cells. Cultivation of islets with IL-18 affected NO production or mitochondrial activity and did not protect from the toxicity mediated by IL-1beta, TNF-alpha, and IFN-gamma. In conclusion, we show for the first time that administration of IL-18, a mediator of the innate immune system, suppresses autoimmune diabetes in nonobese diabetic mice by targeting the Th1/Th2 balance of inflammatory immune reactivity in the pancreas.
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PMID:IL-18 inhibits diabetes development in nonobese diabetic mice by counterregulation of Th1-dependent destructive insulitis. 1041 18

When immunological tolerance breaks down, autoimmune destruction of insulin-producing beta cells in the pancreas can cause insulin-dependent diabetes mellitus. We previously showed that transgenic nonobese diabetic (NOD) mice expressing IL-4 in the pancreas (NOD-IL-4 mice) were protected from insulitis and diabetes. Here we have characterized the avoidance of pathological autoimmunity in these mice. The absence of disease did not result from a lack of T cell priming, because T cells responding to dominant islet Ags were present. These islet Ag-specific T cells displayed a Th2 phenotype, indicating that Th2 responses could account for the observed tolerance. Interestingly, islet Ag-specific Th1 T cells were present and found to be functional, because neutralization of the Th2 effector cytokines IL-4 and IL-10 resulted in diabetes. Histological examination revealed that NOD-IL-4 splenocytes inhibited diabetogenic T cells in cotransfer experiments by limiting insulitis and delaying diabetes. Neutralization of IL-4 in this system abrogated the ability of NOD-IL-4 splenocytes to delay the onset of diabetes. These results indicate that IL-4 expressed in the islets does not prevent the generation of pathogenic islet responses but induces islet Ag-specific Th2 T cells that block the action of diabetogenic T cells in the pancreas.
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PMID:Pancreatic IL-4 expression results in islet-reactive Th2 cells that inhibit diabetogenic lymphocytes in the nonobese diabetic mouse. 1041 77


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