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

To study the expression of HLA-DQ beta chain alleles associated with type 1 diabetes, mAbs were generated from mice immunized with synthetic peptides representing allelic HLA-DQw7 and HLA-DQw8 beta chain sequences. The splenocytes from immunized mice were fused with myeloma cells, either immediately after or following additional in vitro boosting with peptide. Peptide-specific mAbs, predominantly of the IgG isotype, were isolated only from in vitro boosted splenocytes. Immunoblot analysis showed that several of the mAbs cross-reacted with DQ beta chain molecules. One mAb to a peptide representing DQw8 beta position [49-60] specifically recognised the DQw8 beta chain. Three mAbs to a peptide representing DQw8 beta position [39-52] specifically recognised an epitope consisting of Gly-Val-Tyr in position 45-47, i.e., all DQ beta alleles except DQw7 beta (position 45-47: Glu-Val-Tyr) and DQw2 beta (position 45-47; Gly-Glu-Phe). In FACS analysis these mAbs bound lymphocytes with the same specificity as found by immunoblotting analysis. Thus, by combining in vivo and in vitro immunization we have generated a number of epitope specific monoclonal IgG antibodies that distinguish closely related HLA-DQ beta chain alleles in predetermined positions.
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PMID:Production of epitope specific monoclonal IgG antibodies to HLA class II molecules by combining in vivo and in vitro immunization. 137 72

Forty-four children of diabetic mothers aged 10.5 years on an average were examined. Ultrasonography and renography with 123I-hippuran label were used to assess these children's renal status. Various malformations (double kidneys, kidney agenesia, fused of floating kidneys) were detected in 10 patients, in 16 various functional renal disorders were revealed. The authors suppose that maternal juvenile diabetes mellitus, nephropathy, hydramnion, and poor metabolic control during a diabetic pregnancy result in abnormal development of fetal kidneys.
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PMID:[Maternal diabetes mellitus as a risk factor in the development of renal pathology in children]. 807 3

A 65 kDa mycobacterial heat shock protein has been implicated in the development or perpetuation of the inflammatory diseases rheumatoid arthritis (RA) and insulin dependent diabetes mellitus (IDDM). An homology of the mycobacterial hsp65 with human hsp60 (HuHsp60) has been thought to constitute a cross reactive autoimmunizing pathogenetic potential. Study of this cross reactivity with recombinant reagents has been complicated by the fact that recombinant HuHsp60 might be contaminated by the E. coli homologue of HuHsp60, groEL. GroEL and HuHsp60 are very similar in isoelectric point and molecular weight and therefore difficult to separate by classical physicochemical means. Therefore, the HuHsp60 gene was subcloned into the vector, pRSET-B, which resulted in recombinant HuHsp60 protein fused to a 4.5 kDa peptide containing a polyhistidine hexamer. Metal ion affinity for the polyhistidine allowed the rapid and efficient chromatographic separation of the HuHsp60 from groEI. Rabbit antisera were developed to linear peptide epitopes unique to either HuHsp60 or groEL and utilized to discriminate between these proteins during their separation. With the newly prepared HuHsp60 we show that the amount of anti-HuHsp60 autoantibody in both RA and normal sera was too great to be accounted for by cross reacting anti-MbHsp65.
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PMID:Purification of recombinant human Hsp60: use of a GroEL-free preparation to assess autoimmunity in rheumatoid arthritis. 857 22

Autoimmune polyendocrinopathy candidiasis-ectodermal dystrophy (APECED) is a rare recessively inherited disorder caused by mutations in the AIRE (autoimmune regulator) gene. APECED is characterized by variable combinations of endocrine autoimmune diseases such as Addison's disease, hypoparathyroidism, and type 1 diabetes. The AIRE protein contains motifs suggestive of a transcription regulator and can activate transcription of a reporter gene when fused to a heterologous DNA biding domain. In this article, mutation analyses of over 200 APECED patients published by several laboratories are summarized. To date 42 different mutations have been identified. These mutations include nonsense and missense mutations, small insertions and deletions leading into frame shifts, and splice site mutations. Although mutations are spread throughout the coding region of the gene some hotspots emerge, including the more common and recurrent mutations R257X and 967-979del13bp. Some of the identified mutations have been shown to affect subcellular localization or transactivation properties of the protein, thus providing insights into the functional properties of the predicted protein motifs.
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PMID:APECED mutations in the autoimmune regulator (AIRE) gene. 1152 31

Stem cell technologies hold great potential for the treatment of type 1 diabetes, provided that functional transplantable beta-cells can be selectively generated in an efficient manner. Such a process should recapitulate, at least to a certain extent, the embryonic development of beta-cells in vitro. However, progress at identifying the transcription factors involved in beta-cell development has not been accompanied by a parallel success at unraveling the pattern of their instructive extracellular signals. Here we present proof of principle of a novel approach to circumvent this problem, based on the use of the HIV/TAT protein transduction domain. Neurogenin 3 (ngn3), a factor whose expression is essential for pancreatic endocrine differentiation, was fused to the TAT domain. Administration of TAT/ngn3 to cultured pancreatic explants results in efficient uptake, nuclear translocation, and stimulation of downstream reporter and endogenous genes. Consistent with the predicted activity of the protein, e9.5 and e13.5 mouse pancreatic explants cultured in the presence of TAT/ngn3 show an increased level of endocrine differentiation compared with control samples. Our results raise the possibility of sequentially specifying stem/progenitor cells toward the beta-cell lineage, by using the appropriate sequence and combination of TAT-fused transcription factors.
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PMID:TAT-mediated neurogenin 3 protein transduction stimulates pancreatic endocrine differentiation in vitro. 1573 48

Platelets from healthy donors and insuline dependent patients with type 1 diabetes mellitus were examined for proteins specifically interacting in vitro with GST-fused constitutively active (Val12) forms of small GTPases of Rac, Rho and Cdc42. Differential changes in pattern of proteins which bind to these G-proteins in diabetic platelets have been revealed. Obtained results suggest that signalling pathways mediated by Rho GTPases are altered under type I diabetes mellitus. Such changes of actin cytoskeleton regulation may contribute to the higher level of platelet aggregation, which prove to be the etiological background of the late diabetes complications.
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PMID:[Changes in functional state of the low-molecular G-proteins of platelets in type 1 diabetes mellitus]. 1591 22

Cytokines, particularly interleukin (IL)-1beta, have been postulated to cause beta-cell destruction in type 1 diabetes. We tested the efficacy of an IL-1 cytokine trap in counteraction of suppressive and toxic effects after exposure of rat pancreatic islets in vitro to IL-1beta. The IL-1 cytokine trap used herein comprised extracellular domains of the IL-1 receptor accessory protein and the human IL-1 receptor 1 arranged inline and fused to the Fc portion of human IgG1. Groups of isolated rat pancreatic islets were maintained in medium culture with or without IL-1beta (150 pmol/l) for 48 hours in the absence or presence of the IL-1 trap at 1-, 10-, or 100-fold excess the molar concentration of the cytokine. IL-1beta alone induced a strong inhibition of insulin secretion and glucose oxidation rate and a marked increase in medium nitrite accumulation as an indicator of nitric oxide generation. When the IL-1 trap was used at a ratio 10:1 or 100:1, a complete protection against these effects were observed. Moreover, the IL-1 trap (100:1) blocked the increased islet cell death seen in islets treated with a combination of IL-1beta + tumor necrosis factor-alpha + interferon-gamma as well as functional suppression induced by the cytokine combination. In conclusion, we show that addition of an IL-1 trap can protect rat pancreatic islets in vitro against noxious effects induced by IL-1beta. Exploring the IL-1 trap in relevant animal models of type 1 diabetes represents an interesting future intervention strategy.
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PMID:Complete protection against interleukin-1beta-induced functional suppression and cytokine-mediated cytotoxicity in rat pancreatic islets in vitro using an interleukin-1 cytokine trap. 1664 98

In autoimmune (type 1) diabetes, autoreactive lymphocytes destroy pancreatic beta-cells responsible for insulin synthesis. To assess the feasibility of gene therapy for type 1 diabetes, recombinant vaccinia virus (rVV) vectors were constructed expressing pancreatic islet autoantigens proinsulin (INS) and a 55-kDa immunogenic peptide from glutamic acid decarboxylase (GAD), and the immunomodulatory cytokine interleukin (IL)-10. To augment the beneficial effects of recombinant virus therapy, the INS and GAD genes were fused to the C terminus of the cholera toxin B subunit (CTB). Five-week-old non-obese diabetic (NOD) mice were injected once with rVV. Humoral antibody immune responses and hyperglycemia in the infected mice were analyzed. Only 20% of the mice inoculated with rVV expressing the CTB::INS fusion protein developed hyperglycemia, in comparison to 70% of the mice in the uninoculated animal group. Islets from pancreatic tissues isolated from euglycemic mice from this animal group showed no sign of inflammatory lymphocyte invasion. Inoculation with rVV producing CTB::GAD or IL-10 was somewhat less effective in reducing diabetes. Humoral antibody isotypes of hyperglycemic and euglycemic mice from all treated groups possessed similar IgG1/IgG2c antibody titer ratios from 19 to 32 wk after virus inoculation. In comparison with uninoculated mice, 11-wk-old NOD mice injected with virus expressing CTB::INS were delayed in diabetes onset by more than 4 wk. The experimental results demonstrate the feasibility of using rVV expressing CTB::INS fusion protein to generate significant protection and therapy against type 1 diabetes onset and progression.
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PMID:Suppression of hyperglycemia in NOD mice after inoculation with recombinant vaccinia viruses. 1728 79

Type 1 diabetes mellitus (T1DM) is an auto-immune disease while oral administrating its autoantigens could be a treatment of T1DM. To express human insulin gene (ins) in lactic acid bacteria (LAB) for oral vaccine, ins gene was replaced by LAB bias codon and an 8-amino-acid-residue linker peptide forming a beta-turn was designed to link insulin chain A and B. After synthesized by primer annealing method, the whole ins gene was fused with signal peptide sequence SP(Usp45), subcloned into a LAB secretory expressive vector pSW501 and then introduced to Lactococcus lactis (L. lactis) MG1363 and Lactobacillus casei (Lb. casei ) ATCC27092 respectively. Western blot showed that the expression product (SP(Usp45)-INS protein) targeted mainly at the cell wall while little was found in cytoplasm or supernatant. The highest expression level emerged in exponential phase when the optical density at 600nm of the culture was 0.4. The culture of the recombinant strain Lb. casei/pSW501 was administered to non-obese diabetic (NOD) mice orally. ELISA and Western blot results showed that the recombinant strain could induce SP(Usp45)-INS-specific antibodies and raise IL-4 level (38.583 +/- 2.083 pg/mL, P < 0.05) in the mice' s sera. Expression of insulin in the food-grade vehicle LAB could induce oral immune tolerance in NOD mice and protect it from pancreas injury, suggesting it might be a new way to the treatment of T1DM.
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PMID:[Expression of human insulin in lactic acid bacteria and its oral administration in non-obese diabetic mice]. 1827 Dec 51

The peptide P277 contains a target epitope for diabetogenic T cells and it has been used as an ideal target antigen to develop vaccines against type 1 diabetes. A major problem in developing P277 vaccine is its low immunogenicity. Recent applications involving multiple copies of self-peptide in linear alignment and conjugation with carrier proteins appear to increase the immune response. In this study, we designed a method based on isocaudamer technique to repeat tandemly the 24-residue sequence P277, then 6 tandemly repeated copies of the peptide P277 were fused to mycobacterial heat-shock protein 65 to construct a fusion protein HSP65-6xP277 as an immunogen. We examined the effect of the tandem repeats of the peptide P277 in eliciting an immune response by comparing the immunogenicity of the three immunogens: P277, HSP65-P277 and HSP65-6xP277. Immunization of mice with the fusion protein HSP65-6xP277 elicited much higher levels of specific anti-P277 antibodies than with P277 and HSP65-P277, which should suggest that multiple tandem repeats of a certain epitope is an efficient method to overcome the low immunogenicity of self-peptide antigens and the immunogen HSP65-6xP277 might be further developed to a vaccine against type 1 diabetes.
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PMID:Enhanced immunogenicity of peptide P277 by heat shock protein HSP65 vector carrying tandem repeats of P277 to prevent type 1 diabetes in NOD mice. 1847 88


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