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)

This study extends our previous observations that the reovirus type-2(Reo-2) can induce autoimmune insulitis, which may be mediated by T-helper (Th) 1-dependent mechanisms, resulting in diabetes in newborn DBA/1 mice. In this study mRNA expression for Th1-related cytokines including Th1 and Th2 cytokines in splenic cells was examined by reverse transcriptase polymerase chain reaction (RT-PCR) in relation to the development of insulitis. Furthermore, the effect of monoclonal antibody (MoAb) against interleukin (IL)-12(p40) on the development of insulitis and the mRNA expression in the splenic cells was examined. The mRNA expression for IL-12(p40), IL-18, and interferon (IFN)-gamma, but not IL-5, increased in the spleen in parallel with the development of insulitis. The treatment with MoAb to IL-12(p40) reduced the insulitis with diabetes which was associated with a decrease in the mRNA expression for IL-12(p40), IL-18 and IFN-gamma, and an increase of IL-4 mRNA expression in the spleen. The present study suggested that Th1-dominant systemic immune responses, being responsible for the development of autoimmune insulitis, might be induced by IL-12-induced and IL-18-activated mechanisms.
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PMID:Possible involvement of IL-12 in reovirus type-2-induced diabetes in newborn DBA/1 mice. 1142 5

IFN-gamma-mediated Th1 effects play a major role in the pathogenesis of autoimmune diabetes in nonobese diabetic (NOD) mice. We analyzed functional responses of CD4(+) T cells from NOD and B6.G7 MHC congenic mice, which share the H2(g7) MHC region but differ in their non-MHC genetic background. T cells from each strain proliferated equally to panstimulation with T cell lectins as well as to stimulation with glutamic acid decarboxylase 524-543 (self) and hen egg lysozyme 11-23 (foreign) I-A(g7)-binding peptide epitopes. Despite comparable proliferative responses, NOD CD4(+) T cells had significantly increased IFN-gamma intracellular/extracellular protein and mRNA responses compared with B6.G7 T cells as measured by intracellular cytokine analysis, time resolved fluorometry, and RNase protection assays. The increased IFN-gamma production was not due to an increase in the amount of IFN-gamma produced per cell but to an increase in the number of NOD CD4(+) T cells entering the IFN-gamma-producing pathway. The increased IFN-gamma response in NOD mice was not due to increased numbers of activated precursors as measured by activation/memory markers. B6.G7 lymphoid cells demonstrated an absolute decrease in IFN-gamma mRNA, an increase in IL-4 mRNA production, and a significantly decreased IFN-gamma:IL-4 mRNA transcript ratio compared with NOD cells. CD4(+) T cells from C57BL6 mice also showed significantly decreased IFN-gamma production compared with CD4(+) T cells from NOD.H2(b) MHC-congenic mice (which have an H2(b) MHC region introgressed onto an NOD non-MHC background). Therefore, the NOD non-MHC background predisposes to a quantitatively increased IFN-gamma response, independent of MHC class II-mediated T cell repertoire selection, even when compared with a prototypical Th1 strain.
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PMID:Increased entry into the IFN-gamma effector pathway by CD4+ T cells selected by I-Ag7 on a nonobese diabetic versus C57BL/6 genetic background. 1146 93

For gene therapy, tissue targeting of gene delivery systems is required for the maximum efficiency. In this study, we constructed pRIP-IL4 in which the expression of interleukin-4 (IL-4) was driven by the rat insulin promoter. WSLP-pRIP-IL4 complex was characterized by pancreas beta-cell specific and glucose responsive expression of IL-4. pRIP-IL4 was completely retarded at a 6:1 or higher N/P (nitrogen atom of WSLP/phosphate of plasmid) ratio in 1% agarose gel. In addition, WSLP protected plasmid DNA from DNase I for more than 1 h. In cytotoxicity assay, WSLP showed less cytotoxicity than PEI (25000 Da) to mouse insulinoma (MIN6) cells. ELISA showed that pRIP-IL4 expressed much higher levels of IL-4 in MIN6 cells than in NIH3T3 cells. The expression level of IL-4 by pRIP-IL4 increased with increasing concentration of glucose. Also, IL-4 was expressed in a dose-dependent manner. This WSLP-pRIP-IL4 system will be useful in the development of a pancreas specific expression system for the prevention of diabetes without systemic side effects.
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PMID:Cell type specific and glucose responsive expression of interleukin-4 by using insulin promoter and water soluble lipopolymer. 1148 28

In susceptible mice, the heavy metal ion mercury is able to induce a strong immune activation, which resembles a T helper 2 (Th2) type of immune response and is characterized by a polyclonal B cell activation, formation of high levels of IgG1 and IgE antibodies, production of autoantibodies of different specificities and development of renal IgG deposits. In the present study, we analysed the in vivo effects of mercury in nonobese diabetic (NOD) mice, which is believed to develop a spontaneous Th1 cell-mediated autoimmune diabetes similar to type 1 diabetes in humans. Three weeks of treatment with mercury induced a strong Th2 like immune/autoimmune response in NOD mice. This response was characterized by an intensive increase in splenic IgG1 antibody secreting cells, a marked elevation in serum IgE levels, a substantial increase in splenic IL-4 mRNA, but a significant decrease in splenic IFN-gamma mRNA. Mercury-induced IgG1 antibodies were mainly against ssDNA, TNP and thyroglobulin, but not against nucleolar antigen. Moreover, mercury-injected NOD mice developed high titres of IgG1 deposits in the kidney glomeruli. We further tested if the generated Th2 response could interfere with the development of insulitis and diabetes in NOD mice. We found that three weeks of treatment with mercury was also able to significantly suppress the development of insulitis and postpone the onset of diabetes in these mice. Thus, mercury-induced immune activation can counter-regulate the Th1 cell-mediated autoimmune responses and confer a partial protection against autoimmune diabetes in NOD mice.
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PMID:Analysis of mercury-induced immune activation in nonobese diabetic (NOD) mice. 1152 10

Diabetes in non-obese diabetic (NOD) mice is mediated by pathogenic T-helper type 1 (Th1) cells that arise because of a deficiency in regulatory or suppressor T cells. V alpha 14-J alpha 15 natural killer T (NKT) cells recognize lipid antigens presented by the major histocompatibility complex class I-like protein CD1d (refs. 3,4). We have previously shown that in vivo activation of V alpha 14 NKT cells by alpha-galactosylceramide (alpha-GalCer) and CD1d potentiates Th2-mediated adaptive immune responses. Here we show that alpha-GalCer prevents development of diabetes in wild-type but not CD1d-deficient NOD mice. Disease prevention correlated with the ability of alpha-GalCer to suppress interferon-gamma but not interleukin-4 production by NKT cells, to increase serum immunoglobulin E levels, and to promote the generation of islet autoantigen-specific Th2 cells. Because alpha-GalCer recognition by NKT cells is conserved among mice and humans, these findings indicate that alpha-GalCer might be useful for therapeutic intervention in human diseases characterized by Th1-mediated pathology such as Type 1 diabetes.
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PMID:The natural killer T-cell ligand alpha-galactosylceramide prevents autoimmune diabetes in non-obese diabetic mice. 1153 10

Leukocytes infiltrate the pancreatic islets of nonobese diabetic mice, causing beta-cell destruction and autoimmune Type I diabetes. Here, we completely blocked adoptive transfer of diabetes and reduced spontaneous disease incidence from 71% to 17% by simultaneously administering a combination of antibodies directed against alpha4, beta2, and beta7 integrins and their ligands VCAM-1, MAdCAM-1, and ICAM-1 for 52 and 28 days, respectively. CD4 and CD8 T cells and macrophages were excluded from islets and remained entrapped in a peri-islet location as inactive exiles, no longer expressing normal levels of interferon-gamma, interleukin-4, and iNOS. Only IL-10 expression was retained, which could aid immunosuppression. Infiltrating leukocytes retained a peri-islet location, even 215 days following suspension of antibody treatment, potentially forming a barrier to the entry of active, autoantigen-reactive T cells. Combination treatment was effective against spontaneous disease when administered from 7 days of age but ineffective when initiated late in the prediabetic period (day 40 or 70). Nevertheless, anti-alpha4 subunit mAb monotherapy alone was very effective, reducing insulitis to levels similar to those obtained with combinational antibody treatment, suggesting that alpha4 integrins are major receptors contributing to leukocyte infiltration. Treatment with anti-alpha4 integrin antibody retained some therapeutic benefit when administered from days 7, 40, or 70 of age. The results have implications for the treatment of diabetes and provide a unique insight into the fate of disease-forming leukocytes following anti-CAM therapy.
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PMID:Leukocytes infiltrating the pancreatic islets of nonobese diabetic mice are transformed into inactive exiles by combinational anti-cell adhesion therapy. 1159 Jan 86

A functional imbalance in cytokine production resulting in dominance of Th1 over Th2 type response has been suggested to play a critical role in the pathogenesis of type 1 diabetes. In this study the cellular responses to pokeweed mitogen and a panel of specific antigens were analysed by measuring the production of IFN-gamma and IL-4 cytokines at the levels of mRNA expression (expression index=antigen/medium) and protein secretion in culture supernatants. Two enterovirus preparates were included due to the suggested significance of these viruses in the aetiology of type 1 diabetes. The study included 22 children with newly-diagnosed type 1 diabetes, 15 children with longer duration of disease and 20 healthy children. Comparisons were made between age- and sex-matched groups. Newly diagnosed diabetic patients had significantly higher IFN-gamma mRNA expression index (p<0.02) but also higher IL-4 mRNA expression index (p<0.05) in tetanus toxoid stimulated peripheral blood mononuclear cells compared to healthy controls. Also the diabetic patients studied 3-72 months after the diagnosis of type 1 diabetes showed a tendency to higher IFN-gamma mRNA expression index compared to controls (0.05<p<0.1). Enhanced mitogen-stimulated IFN-gamma mRNA expression index was observed in children with newly-diagnosed type 1 diabetes when compared to subjects with longer duration of diabetes (p<0.05). No significant differences were observed in IFN-gamma produced into the culture supernatants. In conclusion, imbalance in both IFN-gamma and IL-4 mRNA levels was demonstrated between diabetic patients and healthy subjects.
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PMID:Induction of interferon-gamma and IL-4 production by mitogen and specific antigens in peripheral blood lymphocytes of Type 1 diabetes patients. 1168 88

Cytotoxic T lymphocyte antigen 4 (CTLA-4 or CD152) is a strong negative regulator of T cell activity. Like CD28 (a positive regulator) it binds to B7-1 and B7-2, and there is no known natural selective ligand. Monoclonal antibodies to CTLA-4 generally have a masking effect, enhancing rather than suppressing responses. However, a single amino acid substitution in B7-1 (W88 > A; denoted B7-1wa) abrogates binding to CD28 but not to CTLA-4. We constructed plasmids encoding B7-1 or B7-1wa, as cell-surface or Ig fusion proteins. In a bound state, B7-1-Ig enhanced CD3-mediated T cell activation, but B7-1wa-Ig was inhibitory, as expected of a CTLA-4 ligand. To alter immunity in vivo, we inoculated mice intramuscularly (i.m.) with a carcinoembryonic antigen (CEA) plasmid. Gene transfer was amplified by electroporation. Co-injection of a B7-1wa (membrane-bound form) plasmid blocked induction of anti-CEA immunity, whereas a B7-1 plasmid was stimulatory. We studied this DNA covaccination method in nonobese diabetic (NOD) mice with autoimmune diabetes. Delivery of either preproinsulin I (PPIns) or B7-1wa cDNA alone did not suppress the autoimmune anti-insulin response of spleen cells. However, co-delivery of B7-1wa and PPIns cDNA abrogated reactivity to insulin and ameliorated disease. Interferon-gamma and interleukin-4 were both depressed, arguing against a Th2 bias. Reactivity to glutamic acid decarboxylase 65, another major islet autoantigen, was not altered and suppressor cells were not identified, suggesting induction of tolerance to insulin by either T cell anergy or deletion. Selective engagement of CTLA-4 through gene transfer represents a novel and powerful way to block autoimmunity specifically.
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PMID:Immunoinhibitory DNA vaccine protects against autoimmune diabetes through cDNA encoding a selective CTLA-4 (CD152) ligand. 1186 Jul 6

Chemokines are important regulators in the development, differentiation, and anatomic location of leukocytes. CC chemokine receptor 5 (CCR5) is expressed preferentially by CD4(+) T helper 1 (Th1) cells. We sought to determine the role of CCR5 in islet allograft rejection in a streptozotocin-induced diabetic mouse model. BALB/c islet allografts transplanted into CCR5(-/-) (C57BL/6) recipients survived significantly longer (mean survival time, 38 +/- 8 days) compared with those transplanted into wild-type control mice (10 +/- 2 days; P < 0.0001). Twenty percent of islet allografts in CCR5(-/-) animals without other treatment survived >90 days. In CCR5(-/-) mice, intragraft mRNA expression of interleukin-4 and -5 was increased, whereas that of interferon-gamma was decreased, corresponding to a Th2 pattern of T-cell activation in the target tissues compared with a Th1 pattern observed in controls. A similar Th2 response pattern was also observed in the periphery (splenocytes responding to donor cells) by enzyme-linked immunosorbent spot assay. We conclude that CCR5 plays an important role in orchestrating the Th1 immune response leading to islet allograft rejection. Targeting this chemokine receptor, therefore, may provide a clinically useful strategy to prevent islet allograft rejection.
Diabetes 2002 Aug
PMID:The role of CC chemokine receptor 5 (CCR5) in islet allograft rejection. 1214 62

We have investigated, in 282 multiplex Caucasian families (the Human Biological Data Interchange Repository), the association of type 1 diabetes with polymorphisms in the IL4R gene. IL4R encodes a subunit of the interleukin-4 receptor, a molecule critical to T-helper cell development. By genotyping eight different IL4R single-nucleotide polymorphisms (SNPs) and identifying haplotypes (complex alleles) in the multiplex type 1 diabetic families who were stratified for HLA genotype, we have observed significant evidence of linkage and association of the IL4R gene to type 1 diabetes. In particular, we have identified a specific haplotype that appears to be protective and observed that this protective effect is strongest among individuals not carrying the HLA DR3/DR4 genotype (which confers the strongest genetic risk for type 1 diabetes). These findings suggest an important role for the IL4R gene in immune-related disease susceptibility and illustrate the value of using multi-SNP haplotype information in association studies.
Diabetes 2002 Nov
PMID:Association of IL4R haplotypes with type 1 diabetes. 1240 28


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