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

Molecular mimicry is one of the mechanisms by which enterovirus infections have been postulated to have a role in the pathogenesis of type 1 diabetes. Immunogenic epitopes in enterovirus capsid protein VP1 and procapsid protein VP0 have sequence similarities with diabetes-associated epitopes in tyrosine phosphatase IA-2/IAR and heat shock protein 60. In the present study, documented enterovirus infection was shown to induce humoral responses, that in 7% and 1% of patients cross-reacted with the known diabetes-associated epitopes in tyrosine phosphatase IAR and heat shock protein 60, respectively. In contrast, none of the children vaccinated against poliomyelitis had antibodies to the diabetes-associated epitope of tyrosine phosphatases IA-2/IAR. The antibody response studied in serum samples from six patients with coxsackievirus A9 infection was mainly targeted to capsid protein VP1. Coxsackievirus A9 infection induced antibodies cross-reacted with one epitope in heat shock protein 60, but not with epitopes derived from other autoantigens. Most diabetic children had high levels of antibodies to both coxsackievirus and poliovirus derived VP1 peptides but the pattern of reactivity did not differ from that seen in healthy children. The reactivity of linear epitopes derived from autoantigens was low in general and associated with the presence of multiple autoantibodies in the patients. Some linear auto-epitopes derived from tyrosine phosphatase IA-2, glutamic acid decarboxylase 65, preproinsulin, and heat shock protein 60 were recognized by sera from diabetic patients, but not by sera from healthy children. In conclusion, enteroviruses may induce immune responses that react with islet cell autoantigens, which is a concern when a putative inactivated enterovirus vaccine is considered.
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PMID:Enterovirus infection may induce humoral immune response reacting with islet cell autoantigens in humans. 1252 55

Type 1 diabetes mellitus results from immune-mediated destruction of pancreatic beta-cells, leading to loss of insulin production. Strategies to prevent or reverse diabetes development include beta-cell protection, regeneration, or replacement. Recent advances in our understanding of the autoimmune process leading to diabetes has generated interest in the potential use of immunomodulatory agents that may collectively be termed vaccines, to prevent type 1 diabetes. Vaccines may work in various ways, including changing the immune response from a destructive (e.g. Th1) to a more benign (e.g. Th2) response, inducing antigen-specific regulatory T cells, deleting autoreactive T cells, or preventing immune cell interaction. To date, most diabetes vaccine development has been in animal models, with relatively few human trials having been completed. A major finding of animal models such as the non-obese diabetic (NOD) mouse is that they are extremely sensitive to diabetes protection, such that many interventions that protect mice are not successful in humans. This is particularly evident for human insulin tolerance studies, including the Diabetes Prevention Trial-1, where no human protection was seen from insulin despite positive NOD results. Further challenges are posed by the need to translate protective vaccine doses in mice to effective human doses. Despite such problems, some promising human vaccine data are beginning to emerge. Recent pilot studies have suggested a beneficial effect in recent-onset human type 1 diabetes from administration of nondepleting anti-CD3 antibodies or a peptide from heat shock protein 60. Given past experience, however, large multicenter, double-blind, controlled confirmatory studies are clearly required and longer term toxicity issues of drugs such as anti-CD3 need to be addressed.Diabetes vaccine development would benefit greatly from the development of reliable surrogate markers of immunoregulation. These would allow faster and more efficient screening of vaccine candidates, and would also assist in the translation of vaccine doses from animal to human studies. Unfortunately, research funding bodies desperate to find a cure are embarking on expensive clinical trials without first addressing important underlying issues such as animal-human dose translation and possible mechanisms of action. No doubt this is due to pressure from their constituency to rapidly find a cure, but unfortunately this approach may slow rather than speed the development of an effective vaccine cure. However, despite the significant hurdles that remain, vaccines remain one of the most promising strategies to prevent type 1 diabetes, with major advantages including convenience, safety, and long-lasting protection.
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PMID:Vaccine therapies for the prevention of type 1 diabetes mellitus. 1295 15

Prevention of type 1 diabetes mellitus requires early intervention in the autoimmune process directed against beta cells of the pancreatic islets of Langerhans. This autoimmune inflammatory process is thought to be caused by the effect of Th1 cells and their secreted cytokines (e.g. interferon) and to be suppressed by Th2-secreted anti-inflammatory cytokines (e.g. IL-4, IL-10). Various methods aimed specifically at halting or modulating this response have been attempted. An alternative method is the re-induction of tolerance towards the putative self antigen that causes the disease. Proposed antigens such as insulin, glutamic acid decarboxilase (GAD) and the heat shock protein 60 (Hsp60)-derived peptide 277 have been used successfully in murine diabetes models and in initial clinical trials in early diabetes patients. Here, we review the results of these trials.
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PMID:Immune modulation for prevention of type 1 diabetes mellitus. 1573 55

DiaPep277, a 24-amino acid peptide based on residues 437 to 460 of heat shock protein 60, is undergoing phase II clinical trials by DeveloGen for the potential treatment and prevention of established and newly diagnosed type 1 diabetes symptoms of the prediabetic state and of latent autoimmune diabetes of the adult.
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PMID:DiaPep277 (DeveloGen). 1625 26

Type 1A diabetes mellitus is caused by specific and progressive autoimmune destruction of the beta cells in the islets of Langerhans whereas the other cell types in the islet (alpha, delta, and PP) are spared. The autoantigens of Type 1A diabetes may be divided into subgroups based on their tissue distributions: Beta-cell-specific antigens like insulin, insulin derivatives, and IGRP (Islet-specific Glucose-6-phosphatase catalytic subunit Related Peptide); neurendocrine antigens such as carboxypeptidase H, insulinoma-associated antigen (IA-2), glutamic acid decarboxylase (GAD65), and carboxypeptidase E; and those expressed ubiquitously like heat shock protein 60 (a putative autoantigen for type 1 diabetes). This review will focus specifically on insulin as a primary autoantigen, an essential target for disease, in type 1A diabetes mellitus. In particular, immunization with insulin peptide B:9-23 can be used to induce insulin autoantibodies and diabetes in animal models or used to prevent diabetes. Genetic manipulation of the insulin 1 and 2 genes reciprocally alters development of diabetes in the NOD mouse, and insulin gene polymorphisms are important determinants of childhood diabetes. We are pursuing the hypothesis that insulin is a primary autoantigen for type 1 diabetes, and thus the pathogenesis of the disease relates to specific recognition of one or more peptides.
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PMID:Insulin as a primary autoantigen for type 1A diabetes. 1629 23

To identify important anti-islet T-cells and their target antigen(s), we have isolated and characterized seventeen human T-cell clones which are reactive to an extract of rat insulinoma (RIN) cells from three children with new onset type 1 diabetes mellitus (T1D). Of these 17 clones, 15 were found tissue specific. Six of eight tested tissue specific clones did not recognize known islet antigens such as GAD, 52 kDa islet protein, insulin, ICA512, and heat shock protein 60 (hsp60), suggesting that these clones recognize an autoantigen not previously identified. All tested clones were phenotypically CD4 and functionally Th0 or Th0/Th1 cells. One RIN extract reactive clone (2E9) recognized hsp60 and was CD4 and TCR alpha/beta positive. This clone also proliferated in response to human and rat islets suggesting that the antigen is conserved between species. This clone and 75% of all the tested RIN reactive clones exhibited anti-islet cytotoxicity by lysing target cells coated with RIN extract. HLA DR determinants may play a role in this cytotoxic activity since preincubation with HLA DR antibody decreased the anti-islet cytoxicity of the two tested clones. In conclusion, we have isolated RIN reactive CD4+T-cell clones from diabetic subjects, six of which appears tissue specific and non-reactive to putative important islet antigens, and in turn may be recognizing yet undiscovered islet antigens. The high frequency anti-islet cytotoxic properties of the islet reactive clones provides evidence for a role of CD4+ cytotoxic T-lymphocytes in the diabetic process. Further, the isolation of hsp60 reactive clone with anti-islet cytotoxic properties suggests that cell mediated immunity against hsp60 may be important in the pathogenesis of diabetes.
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PMID:Characterization of anti-islet cytotoxic human T-cell clones from patients with type 1 diabetes mellitus. 1689 Dec 21

Peptide p277 is a 24-amino acid fragment of the heat shock protein 60 molecule, first discovered to be an antigen for diabetogenic T-cell clones in non-obese diabetic (NOD) mice. Therapeutic vaccination with p277 can arrest the spontaneous diabetogenic process both in NOD mice and in humans associated with a T(h)1 to T(h)2 cytokine shift specific for the autoimmune T cells. We now report that p277 can directly signal human T cells via innate toll-like receptor (TLR)-2, leading to up-regulation of integrin-mediated adhesion to fibronectin, and inhibition of chemotaxis to the chemokine SDF-1alpha in vitro. Resting CD45RA(+) T cells responded to lower concentrations of p277 than resting CD45RO(+) T cells, but activation of CD45RO(+) T cells greatly increased their sensitivity to p277. Mouse T cells, but not macrophages, were also sensitive to the innate effects of peptide p277, and adoptive transfer of diabetes by splenic T cells from NOD mice could be inhibited by p277 treatment before transfer. Thus, T cells do respond innately to p277, and signaling by soluble p277 through TLR2 could contribute to the treatment of type 1 diabetes; p277 may stop the destruction of beta cells by signaling in concert both innate and adaptive receptors on T cells.
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PMID:Peptide p277 of HSP60 signals T cells: inhibition of inflammatory chemotaxis. 1689 23

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

Mucosal administration of autoantigen HSP65 can induce anti-inflammatory immune response and decrease organ-specific inflammation and disease in several models of autoimmunity, such as arthritis and atherosclerosis. We have been interested in whether the HSP65 serves as an immunogenic carrier for a diabetogenic peptide P277 can also induce anti-inflammatory immune response in NOD mice by mucosal administration. Thus, the dual functions of anti-type 1 diabetes of HSP65 and P277 will be obtained. To test this hypothesis, we examined the effect of intranasal vaccination with P277 tandem repeat sequences carried by HSP65 in the absence of adjuvants on autoimmune diabetes in NOD mice. We found a significant decrease in the incidence of diabetes, inhibition of insulitis, reduction in IgG2a isotype antibodies to P277 and proinflammatory cytokines IFN-gamma and IL-2 secretion, increased IgG1, IgG2b subclass antibodies to P277 and anti-inflammatory cytokines IL-10 and IL-4 secretion, and reduced proliferation in nasal administration of the fusion protein HSP65-6xP277. Our results demonstrate that HSP65 may serve as a particularly advantageous carrier for P277-based vaccines and mucosal administration may be a therapeutic approach for treatment of type 1 diabetes.
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PMID:HSP65 serves as an immunogenic carrier for a diabetogenic peptide P277 inducing anti-inflammatory immune response in NOD mice by nasal administration. 2022 47

A key feature of the immune system is its ability to discriminate self from nonself. Breakdown in any of the mechanisms that maintain unresponsiveness to self (a state known as self-tolerance) contributes to the development of autoimmune conditions. Recent studies in mice show that CD8(+) T cells specific for the unconventional MHC class I molecule Qa-1 bound to peptides derived from the signal sequence of Hsp60 (Hsp60sp) contribute to self/nonself discrimination. However, it is unclear whether they exist in humans and play a role in human autoimmune diseases. Here we have shown that CD8(+) T cells specific for Hsp60sp bound to HLA-E (the human homolog of Qa-1) exist and play an important role in maintaining peripheral self-tolerance by discriminating self from nonself in humans. Furthermore, in the majority of type 1 diabetes (T1D) patients tested, there was a specific defect in CD8(+) T cell recognition of HLA-E/Hsp60sp, which was associated with failure of self/nonself discrimination. However, the defect in the CD8(+) T cells from most of the T1D patients tested could be corrected in vitro by exposure to autologous immature DCs loaded with the Hsp60sp peptide. These data suggest that HLA-E-restricted CD8(+) T cells may play an important role in keeping self-reactive T cells in check. Thus, correction of this defect could be a potentially effective and safe approach in the therapy of T1D.
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PMID:HLA-E-restricted regulatory CD8(+) T cells are involved in development and control of human autoimmune type 1 diabetes. 2087 6


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