Induction of Autoimmune Diabetes by Oral Administration of Autoantigen

Blanas, Effrossini; Carbone, Federico; Allison, Janette; Miller, J. F. A. P.; Heath, William R.

doi:10.1126/science.274.5293.1707

Cited by 241 publications

(163 citation statements)

References 24 publications

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“…Using MOG-induced EAE in marmoset monkeys, it was noted that the secondary injection of soluble MOG into MOG: CFA-preimmunized animals caused a Th2 shift in the T cell response, but eventually resulted in a delayed and more severe form of EAE (44). These and other experiments (45), including induction of EAE in some rat strains using neuroantigen/IFA injections (46), have raised significant concern regarding the potential pathogenicity of therapies aimed at exploiting active/regulatory immune mechanisms for treatment of autoimmune diseases. These concerns might be even more substantial when the extracellular target Ags used are not protected from autoantibodies by anatomic barriers such as the BBB.…”

Section: Revisiting Tolerance Induced By Autoantigen In Incompletementioning

confidence: 90%

Revisiting Tolerance Induced by Autoantigen in Incomplete Freund’s Adjuvant

Heeger

Forsthuber

Shive

et al. 2000

The Journal of Immunology

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Injection of autoantigens in IFA has been one of the most effective ways of preventing experimental, T cell-mediated, autoimmune disease in mice. The mechanism that underlies this protection has, however, remained controversial, with clonal deletion, induction of suppressor cells or of type 2 immunity being implicated at one time or another. Using high resolution enzyme-linked immunospot (ELISPOT) analysis, we have revisited this paradigm. As models of autoimmunity against sequestered and readily accessible autoantigens, we studied experimental allergic encephalomyelitis, induced by myelin oligodendrocyte glycoprotein, proteolipid protein, myelin basic protein, and renal tubular Ag-induced interstitial nephritis. We showed that the injection of each of these Ags in IFA was immunogenic and CD4 memory cells producing IL-2, IL-4, and IL-5, but essentially no IFN-γ. IgG1, but not IgG2a, autoantibodies were produced. The engaged T cells were not classic Th2 cells in that IL-4 and IL-5 were produced by different cells. The IFA-induced violation of self tolerance, including the deposition of specific autoantibodies in the respective target organs, occurred in the absence of detectable pathology. Exhaustion of the pool of naive precursor cells was shown to be one mechanism of the IFA-induced tolerance. In addition, while the IFA-primed T cells acted as suppressor cells, in that they adoptively transferred disease protection, they did not interfere with the emergence of a type 1 T cell response in the adoptive host. Both active and passive tolerance mechanisms, therefore, contribute to autoantigen:IFA-induced protection from autoimmune disease.

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Section: Revisiting Tolerance Induced By Autoantigen In Incompletementioning

confidence: 90%

Revisiting Tolerance Induced by Autoantigen in Incomplete Freund’s Adjuvant

Heeger

Forsthuber

Shive

et al. 2000

The Journal of Immunology

View full text Add to dashboard Cite

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“…Hence, it is not surprising that oral antigen dosing was recently even found in settings particularly to exacerbate autoimmune disease [35,36].…”

Section: Discussionmentioning

confidence: 99%

Oral insulin for diabetes prevention in NOD mice: potentiation by enhancing Th2 cytokine expression in the gut through bacterial adjuvant

et al. 1997

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“…Some experimental studies have shown, however, that insulin may exacerbate the disease when combined with an infectious agent (41). Also, in a transgenic mouse model, oral administration of an antigen expressed in ␤-cells induced diabetes (42). Age of exposure also seems important because oral administration of myelin basic protein (MBP) to neonate rats primes for immune responses and enhances experimental autoimmune encephalomyelitis (EAE), whereas oral exposure in adult rats results in disease suppression (43).…”

Section: A B C Dmentioning

confidence: 99%

Effect of cow's milk exposure and maternal type 1 diabetes on cellular and humoral immunization to dietary insulin in infants at genetic risk for type 1 diabetes. Finnish Trial to Reduce IDDM in the Genetically at Risk Study Group.

et al. 2000

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Type 1 diabetes is considered to be a T-cell-mediated autoimmune disease in which insulin-producing ␤-cells are destroyed. Immunity to insulin has been suggested to be one of the primary autoimmune mechanisms leading to islet cell destruction. We have previously shown that the first immunization to insulin occurs by exposure to bovine insulin (BI) in cow's milk (CM) formula. In this study, we analyzed the development of insulinspecific T-cell responses by proliferation test, emergence of insulin-binding antibodies by enzyme immunoassay, and insulin autoantibodies by radioimmunoassay in relation to CM exposure and family history of type 1 diabetes in infants with a first-degree relative with type 1 diabetes and increased genetic risk for the disease. The infants were randomized to receive either an adapted CM-based formula or a hydrolyzed casein (HC)-based formula after breast-feeding for the first 6-8 months of life. At the age of 3 months, both cellular and humoral responses to BI were higher in infants exposed to CM formula than in infants fully breast-fed (P = 0.015 and P = 0.007). IgG antibodies to BI were higher in infants who received CM formula than in infants who received HC formula at 3 months of age (P = 0.01), but no difference in T-cell responses was seen between the groups. T-cell responses to BI at 9 months of age (P = 0.05) and to human insulin at 12 (P = 0.014) and 24 months of age (P = 0.009) as well as IgG antibodies to BI at 24 months of age (P = 0.05) were lower in children with a diabetic mother than in children with a diabetic father or a sibling, suggesting possible tolerization to insulin by maternal insulin therapy. The priming of insulin-specific humoral and T-cell immunity occurs in early infancy by dietary insulin, and this phenomenon is influenced by maternal type 1 diabetes.

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Induction of Autoimmune Diabetes by Oral Administration of Autoantigen

Cited by 241 publications

References 24 publications

Revisiting Tolerance Induced by Autoantigen in Incomplete Freund’s Adjuvant

Revisiting Tolerance Induced by Autoantigen in Incomplete Freund’s Adjuvant

Oral insulin for diabetes prevention in NOD mice: potentiation by enhancing Th2 cytokine expression in the gut through bacterial adjuvant

Effect of cow's milk exposure and maternal type 1 diabetes on cellular and humoral immunization to dietary insulin in infants at genetic risk for type 1 diabetes. Finnish Trial to Reduce IDDM in the Genetically at Risk Study Group.

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