Oral Exposure to Diabetes-Promoting Food or Immunomodulators in Neonates Alters Gut Cytokines and Diabetes

Scott, Fraser W.; Rowsell, Paul R.; Wang, Gensheng; Burghardt, Karolina; Kolb, Hubert; Flohé, Stefanie B.

doi:10.2337/diabetes.51.1.73

Cited by 76 publications

(70 citation statements)

References 24 publications

(24 reference statements)

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“…A gluten-free (GF) diet has been shown to have a protective effect against the development of T1D. It has been demonstrated that a GF diet in nonobese diabetic (NOD) mice reduces diabetes incidence from 64 to 15% [1], and similar results have been obtained with biobreeding rats [2]. Increased intestinal permeability occurs prior to the onset of T1D in both spontaneous animal models and human disease [3,4].…”

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confidence: 60%

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Dietary gluten increases natural killer cell cytotoxicity and cytokine secretion

et al. 2014

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Dietary gluten influences the development of type 1 diabetes in nonobese diabetic (NOD) mice and biobreeding rats, and has been shown to influence a wide range of immunological factors in the pancreas and gut. In the present study, the effects of gluten on NK cells were studied in vitro and in vivo. We demonstrated that gliadin increased direct cytotoxicity and IFN-γ secretion from murine splenocytes and NK cells toward the pancreatic beta-cell line MIN6 cells. Additionally, stimulation of MIN6 cells led to a significantly increased proportion of degranulating C57BL/6 CD107a + NK cells. Stimulation of C57BL/6 pancreatic islets with gliadin significantly increased secretion of IL-6 more than ninefold. In vivo, the gluten-containing diet led to a higher expression of NKG2D and CD71 on NKp46 + cells in all lymphoid organs in BALB/c and NOD mice compared with the gluten-free diet. Collectively, our data suggest that dietary gluten increases murine NK-cell activity against pancreatic beta cells. This mechanism may contribute to development of type 1 diabetes and explain the higher disease incidence associated with gluten intake in NOD mice.Keywords: C56BL/6 mice r Gliadin r Gluten r NK cells r NOD mice r Type 1 diabetes Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionDietary gluten is the initiating factor in the development of celiac disease (CD), however, an association between CD and type 1 diabetes (T1D) has been established. A gluten-free (GF) diet has been shown to have a protective effect against the development of T1D. It has been demonstrated that a GF diet in nonobese diabetic (NOD) mice reduces diabetes incidence from 64 to 15% [1], and similar results have been obtained with biobreeding rats [2]. Increased intestinal permeability occurs prior to the onset of T1D in both spontaneous animal models and human disease [3,4]. Patients with both CD and T1D diseases carry high-risk HLA alleles [5], and approximately 10% of T1D patients have anCorrespondence: Jesper Larsen e-mail: jelars@gmail.com increased prevalence of CD [6]. Moreover, T1D rarely develops after diagnosed CD, which may be because of the protective effect of a GF diet [7]. A recently published case report describes a boy with T1D who was able to maintain a low fasting blood glucose level without insulin therapy for more than 20 months after the time of diagnosis by adhering to a GF diet [8]. Lately, it has also been suggested that a family of gluten proteins known as gliadins may contribute directly to beta-cell hyperactivity, as enzymatically digested gliadin and a 33-mer gliadin fragment increase insulin secretion from beta cells by affecting the K ATP channel current [9]. This process could induce increased Ag expression of the beta-cell surface and prevent beta-cell rest [10]. Gliadin has been shown to stimulate several components of the adaptive immune system, such as Treg cells, Th17 cells, and DCs [11,12]. Gliadin fragments have also been shown to stimulate TLR4 a...

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confidence: 60%

“…MIN6 cells [28] (kindly provided by J. Miyazaki, Osaka University) were grown at 37°C and 5% CO 2 Gliadin was enzymatically digested, prepared, and tested as described in [9]. In gliadin stimulation experiments, the cells were exposed to 300 μg/mL gliadin digest for 24 h, unless otherwise noted.…”

Section: Cell Culturementioning

confidence: 99%

Dietary gluten increases natural killer cell cytotoxicity and cytokine secretion

et al. 2014

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“…In preliminary experiments we have found that oral anti-CD3 mAb is effective in preventing diabetes when given to neonatal NOD mice (R.M., M. Abraham, unpublished observations). Although the cause of type 1 diabetes is not known, there is the suggestion that the gut may play a role as the site at which newborns are sensitized to islet antigens related to cross-reactivity with cow milk and/or defective mechanisms of mucosal tolerance (22)(23)(24). Oral anti-CD3 mAb may thus serve to boost the natural induction of regulatory T-cells at the gut mucosa.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Autoimmune Diabetes by Oral Administration of Anti-CD3 Monoclonal Antibody

et al. 2007

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Anti-CD3 monoclonal antibody (mAb) has been shown to induce tolerance and to be an effective treatment for diabetes both in animal models and in human trials. We have shown that anti-CD3 mAb given orally is biologically active in the gut and suppresses experimental autoimmune encephalitis by the induction of a regulatory T-cell that expresses latency-associated peptide (LAP) on its surface. In the present study, we investigated the effect of oral anti-CD3 mAb on the prevention of autoimmune diabetes in AKR mice in which the low-dose streptozocin (STZ) model induces autoimmunity to the ␤-cells of the islets. We found that oral anti-CD3 mAb given at doses of 50 and 250 g/feeding suppressed the incidence of diabetes in this model with the best effects seen at the 50 g/dose. Associated with suppression, we observed decreased cell prolif- I mmunological tolerance is mediated by a number of mechanisms, and it is generally believed that autoimmune processes such as those that occur in type 1 diabetes are in some way related to defects in immunological tolerance (1). One approach for the treatment of autoimmunity has been the parenteral administration of anti-CD3 monoclonal antibody (mAb), which is efficacious in animal models of autoimmunity including autoimmune diabetes (2-7) and experimental allergic encephalomyelitis (EAE) (8,9) and in human trials of type 1 diabetes (10 -12). Intravenous (IV) anti-CD3 mAb is an approved therapy for transplant rejection in humans (13). We have been interested in immune therapy of autoimmune diseases by mucosal administration of autoantigens designed to induce regulatory T-cells (14,15). We have recently found that oral anti-CD3 mAb is biologically active in the gut and induces a CD4 ϩ CD25 Ϫ latency-associated peptide (LAP) ϩ regulatory T-cell that suppresses EAE in a transforming growth factor (TGF)-␤-dependent fashion (16). LAP is the NH 2 -terminal domain of the TGF-␤ precursor peptide; it remains noncovalently associated with TGF-␤ peptide after cleavage and forms the latent TGF-␤ complex. We previously identified CD4 ϩ CD25 Ϫ LAP ϩ T-cells that suppress colitis by a TGF-␤-dependent mechanism (17).Given this finding, we investigated the effect of oral anti-CD3 mAb in AKR mice on the prevention of autoimmune diabetes using the low-dose streptozocin (STZ) model, which induces autoimmunity to ␤-cells (18). Diabetes in the STZ model can be prevented by administration of anti-T-cell monoclonal antibodies, and diabetes can be adoptively transferred with splenocytes from diabetic animals (19). This model is useful for the testing of novel immunotherapeutic interventions because hyperglycemia and insulitis can be easily induced in a relatively short period of time in a high percentage of animals. Furthermore, treatment can be given before irreversible tissue damage and before T-cells have become sensitized to islet antigens. It was previously shown by Herold et al. (2) that IV anti-CD3 mAb is effective in the STZ model. Given our results in the EAE model, we investigated the effect of o...

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“…Already in the first week of life, oral feeding of a diabetogenic diet decreased the pro-/anti-inflammatory cytokine ratio in the gut which later in life significantly inhibited diabetes in bio-breeding rats. 30 Furthermore, the optimal prevention of diabetes by oral administration of a bacterial extract was observed before six weeks of age in non-obese diabetic (NOD) mice. 31 These interventions are most prominent in the pre-diabetic stage, suggesting that early life events during microbial colonization and development of the immune system are relevant in modifying autoimmune diabetes risk.…”

Section: Future Applicationmentioning

confidence: 99%

Customizing laboratory mice by modifying gut microbiota and host immunity in an early “window of opportunity”

2013

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Oral Exposure to Diabetes-Promoting Food or Immunomodulators in Neonates Alters Gut Cytokines and Diabetes

Cited by 76 publications

References 24 publications

Dietary gluten increases natural killer cell cytotoxicity and cytokine secretion

Dietary gluten increases natural killer cell cytotoxicity and cytokine secretion

Inhibition of Autoimmune Diabetes by Oral Administration of Anti-CD3 Monoclonal Antibody

Customizing laboratory mice by modifying gut microbiota and host immunity in an early “window of opportunity”

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