Glutamic acid decarboxylase epitope protects against autoimmune diabetes through activation of Th2 immune response and induction of possible regulatory mechanism

Gong, Zhaohui; Pan, Lin; Le, Yanping; Liu, Qiong; Zhou, Mi; Wei, Xing; Zhuo, Ren‐Xi; Wang, Shaomin; Guo, Junming

doi:10.1016/j.vaccine.2010.04.005

Cited by 14 publications

(13 citation statements)

References 50 publications

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“…Over the last 15 years, however, the progress on diabetes suppression with CTB‐based oral fusion vaccines has been modest. Since early reports where 50% diabetes suppression was demonstrated , to our knowledge the strongest suppression to date (60%) has been achieved using GAD peptide 531–545 fused as trimer to CTB as mentioned above . These data indicate that solid diabetes suppression using CTB as fusion partner has remained difficult to obtain.…”

Section: Discussionmentioning

confidence: 95%

Cholera toxin subunit B peptide fusion proteins reveal impaired oral tolerance induction in diabetes‐prone but not in diabetes‐resistant mice

et al. 2013

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The B subunit of cholera toxin (CTB) has been used as adjuvant to improve oral vaccine delivery in type 1 diabetes. The effect of CTB/peptide formulations on antigen-specific CD4 T cells has remained largely unexplored. We investigated by tetramer analysis how oral delivery of CTB fused to 2 CD4 T cell epitopes, the BDC-2.5 T cell 2.5mi mimotope and glutamic acid decarboxylase (GAD) 286–300, affected diabetogenic CD4 T cells in NOD mice. CTB-2.5mi activated 2.5mi+ T cells when administered intraperitoneally and generated Ag-specific Foxp3+ Treg and Th2 cells following intragastric delivery. While 2.5mi+ and GAD-specific T cells were tolerized in diabetes resistant NODxB6.Foxp3EGFP F1 and NOR mice, this did not occur in NOD mice. This indicated NOD mice had a recessive genetic resistance to induce oral tolerance to both CTB-fused epitopes. Contrarily to NODxB6.Foxp3EGFP F1 mice, oral treatment in NOD mice lead to strong 2.5mi+ T cell activation and the sequestration of these cells to the effector-memory pool. Oral treatment of NOD mice with CTB-2.5mi failed to prevent diabetes. These findings underline the importance of investigating the effect of oral vaccine formulations on diabetogenic T cells as in selected cases they may have counterproductive consequences in human patients.

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Section: Discussionmentioning

confidence: 95%

Cholera toxin subunit B peptide fusion proteins reveal impaired oral tolerance induction in diabetes‐prone but not in diabetes‐resistant mice

et al. 2013

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“…Other groups have shown suppression of diabetes in NOD mice by the oral tolerance approach, but specific strategies had to be developed to circumvent the fact that tolerance induction by antigen feeding is impaired in these animals. Some studies reported that antigenic peptides, neonatal administration of insulin via the oral route, oral CD3‐specific mAb treatment, or repertoire manipulation by backcrossing to other strains of mice were used to delay onset and reduce incidence of diabetes in these mice.…”

Section: Discussionmentioning

confidence: 99%

Frontline Science: Abnormalities in the gut mucosa of non-obese diabetic mice precede the onset of type 1 diabetes

Miranda

Oliveira

Torres

et al. 2019

Journal of Leukocyte Biology

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Alterations in the composition of the intestinal microbiota have been associated with development of type 1 diabetes (T1D), but little is known about changes in intestinal homeostasis that contribute to disease pathogenesis. Here, we analyzed oral tolerance induction, components of the intestinal barrier, fecal microbiota, and immune cell phenotypes in non‐obese diabetic (NOD) mice during disease progression compared to non‐obese diabetes resistant (NOR) mice. NOD mice failed to develop oral tolerance and had defective protective/regulatory mechanisms in the intestinal mucosa, including decreased numbers of goblet cells, diminished mucus production, and lower levels of total and bacteria‐bound secretory IgA, as well as an altered IEL profile. These disturbances correlated with bacteria translocation to the pancreatic lymph node possibly contributing to T1D onset. The composition of the fecal microbiota was altered in pre‐diabetic NOD mice, and cross‐fostering of NOD mice by NOR mothers corrected their defect in mucus production, indicating a role for NOD microbiota in gut barrier dysfunction. NOD mice had a reduction of CD103+ dendritic cells (DCs) in the MLNs, together with an increase of effector Th17 cells and ILC3, as well as a decrease of Th2 cells, ILC2, and Treg cells in the small intestine. Importantly, most of these gut alterations precede the onset of insulitis. Disorders in the intestinal mucosa of NOD mice can potentially interfere with the development of T1D due the close relationship between the gut and the pancreas. Understanding these early alterations is important for the design of novel therapeutic strategies for T1D prevention.

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“…The CTB fused to three copies of peptide 531–545 (3p531) from GAD65 when fed orally to NOD mice showed less pancreatic inflammation and delayed diabetes development. The incidence of diabetes was 39% (7/18) in CTB-3p531 fusion protein administered in 35 weeks old NOD mice [67]. Although upon oral administration of purified protein or peptide disease symptoms were improved, they are degraded and hydrolyzed before reaching the absorption site and therefore is not a reproducible option for oral delivery of therapeutic proteins.…”

Section: Current Delivery Methods For Biopharmaceutical Proteins Amentioning

confidence: 99%

Oral delivery of human biopharmaceuticals, autoantigens and vaccine antigens bioencapsulated in plant cells

Kwon

Verma

Singh

et al. 2013

Advanced Drug Delivery Reviews

129

146

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Among 12 billion injections administered annually, unsafe delivery leads to >20 million infections and >100 million reactions. In an emerging new concept, freeze-dried plant cells (lettuce) expressing vaccine antigens/biopharmaceuticals are protected in the stomach from acids/enzymes but are released to the immune or blood circulatory system when plant cell walls are digested by microbes that colonize the gut. Vaccine antigens bioencapsulated in plant cells upon oral delivery after priming, conferred both mucosal and systemic immunity and protection against bacterial, viral or protozoan pathogens or toxin challenge. Oral delivery of autoantigens was effective against complications of type 1diabetes and hemophilia, by developing tolerance. Oral delivery of proinsulin or exendin-4 expressed in plant cells regulated blood glucose levels similar to injections. Therefore, this new platform offers a low cost alternative to deliver different therapeutic proteins to combat infectious or inherited diseases by eliminating inactivated pathogens, expensive purification, cold storage/transportation and sterile injections.

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Glutamic acid decarboxylase epitope protects against autoimmune diabetes through activation of Th2 immune response and induction of possible regulatory mechanism

Cited by 14 publications

References 50 publications

Cholera toxin subunit B peptide fusion proteins reveal impaired oral tolerance induction in diabetes‐prone but not in diabetes‐resistant mice

Cholera toxin subunit B peptide fusion proteins reveal impaired oral tolerance induction in diabetes‐prone but not in diabetes‐resistant mice

Frontline Science: Abnormalities in the gut mucosa of non-obese diabetic mice precede the onset of type 1 diabetes

Oral delivery of human biopharmaceuticals, autoantigens and vaccine antigens bioencapsulated in plant cells

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