Progression From Insulitis to β-Cell Destruction in NOD Mouse Requires L3T4+ T-Lymphocytes

Charlton, Brett; Mandel, T. E.

doi:10.2337/diab.37.8.1108

Cited by 49 publications

(30 citation statements)

References 11 publications

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“…Each pancreas was fixed with 10% buffered formalin and embedded in paraffin, and 5-m sections were stained with hematoxylin and eosin. The degree of insulitis was evaluated on a blind basis by using a standardized scoring system described by others (20).…”

Section: Determination Of Biological Activity Of Plant Rmil-4mentioning

confidence: 99%

Induction of oral tolerance to prevent diabetes with transgenic plants requires glutamic acid decarboxylase (GAD) and IL-4

Huang

Yin

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

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Induction of specific immunological unresponsiveness by feeding protein antigens is termed oral tolerance and may be a potential therapy for autoimmune diseases. Whereas oral tolerance therapy may be both simple and effective, the requirement for large amounts of protein will limit clinical testing of autoantigens, which are difficult to produce. We have previously demonstrated transgenic plant production and direct oral delivery of a ␤ cell autoantigen murine GAD67 to prevent autoimmune diabetes in nonobese diabetic mice. Mucosal adjuvants such as cholera toxin B subunit may lower the level of autoantigen required, but the development of neutralizing mucosal antibody responses may limit usefulness in enhancing long-term oral tolerance. IL-4, being an endogenous protein, would avoid this result and possibly enhance oral tolerance but has not been tested as a mucosal adjuvant. In this study, human GAD65 (hGAD65), as well as murine IL-4, was expressed in transgenic plants for feeding trials. Both IL-4 and hGAD65 plant tissue were required to protect nonobese diabetic mice from diabetes, and no benefit was found if either was used alone. Combined therapy enhanced levels of IgG1 anti-GAD antibodies, increased splenocyte IL-4͞IFN-␥ cytokine responses, and produced protective regulatory T cells. These results demonstrate that orally administered plant IL-4 remains biologically active and is synergistic when given with hGAD65 in inducing robust oral immune tolerance. Using transgenic plants expressing IL-4 and GAD65 may be a novel clinical approach to the prevention of human type 1 diabetes by oral tolerance.

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Section: Determination Of Biological Activity Of Plant Rmil-4mentioning

confidence: 99%

Induction of oral tolerance to prevent diabetes with transgenic plants requires glutamic acid decarboxylase (GAD) and IL-4

Huang

Yin

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

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“…For histological analysis, female wild-type and IL-1R-deficient mice were killed at 120 days of age, the pancreas was removed and placed in Bouin's fixative, and 5-m paraffin-embedded sections were cut at 40-m intervals. Hemotoxylin and eosin-stained sections were scored for insulitis using a 0 -4 scoring system as previously described (29). The scores are expressed as percentage infiltration.…”

Section: Methodsmentioning

confidence: 99%

IL-1 Receptor Deficiency Slows Progression to Diabetes in the NOD Mouse

et al. 2004

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“…5-m paraffin-embedded sections were cut and stained with hemotoxylin and eosin. Insulitis was scored on three sections cut 40 m apart on a 0-4 scale as described (46). Three mice were analyzed per group, with ‫ف‬ 100 islets scored in each group.…”

Section: Methodsmentioning

confidence: 99%

IFN-gamma action on pancreatic beta cells causes class I MHC upregulation but not diabetes.

Thomas¹,

Parker²,

Schreiber³

et al. 1998

J. Clin. Invest.

122

125

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We have generated transgenic nonobese diabetic (NOD) mice expressing dominant negative mutant IFN-␥ receptors on pancreatic beta cells to investigate whether the direct effects of IFN-␥ on beta cells contribute to autoimmune diabetes. We have also quantitated by flow cytometry the rise in class I MHC on beta cells of NOD mice with increasing age and degree of islet inflammatory infiltrate. Class I MHC expression increases gradually with age in wild-type NOD mice; however, no such increase is observed in the transgenic beta cells. The transgenic mice develop diabetes at a similar rate to that of wild-type animals. This study dissociates class I MHC upregulation from progression to diabetes, shows that the rise in class I MHC is due to local IFN-␥ action, and eliminates beta cells as the targets of IFN-␥ in autoimmune diabetes. ( J. Clin. Invest. 1998. 102:1249-1257.)

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Progression From Insulitis to β-Cell Destruction in NOD Mouse Requires L3T4+ T-Lymphocytes

Cited by 49 publications

References 11 publications

Induction of oral tolerance to prevent diabetes with transgenic plants requires glutamic acid decarboxylase (GAD) and IL-4

Induction of oral tolerance to prevent diabetes with transgenic plants requires glutamic acid decarboxylase (GAD) and IL-4

IL-1 Receptor Deficiency Slows Progression to Diabetes in the NOD Mouse

IFN-gamma action on pancreatic beta cells causes class I MHC upregulation but not diabetes.

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