Prevention of insulin-dependent diabetes mellitus: an overview of three trials

Schatz, Desmond; Rogers, D. G.; Brouhard, Ben H.

doi:10.3949/ccjm.63.5.270

Cited by 18 publications

(13 citation statements)

References 8 publications

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“…Current strategies include nicotinamide, cyclosporin and other immunosuppressive agents although the side effects of the latter two agents make them unsuitable for routine use. More recently, there has been great interest in inducing tolerance using oral and parenteral insulin [88,90] as well as oral GAD which has been successful in preventing autoimmune disease in non-obese diabetic (NOD) mice [91]. The use of oral insulin is currently being explored in DPT-1 [88].…”

Section: Screening For Diabetesmentioning

confidence: 99%

“…More recently, there has been great interest in inducing tolerance using oral and parenteral insulin [88,90] as well as oral GAD which has been successful in preventing autoimmune disease in non-obese diabetic (NOD) mice [91]. The use of oral insulin is currently being explored in DPT-1 [88]. As GAD65 can be produced in large amounts through recombinant gene technology, it should soon be possible to test whether treating humans with oral GAD can halt the autoimmune process, and indeed, progression to overt clinical Type I diabetes.…”

Section: Screening For Diabetesmentioning

confidence: 99%

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Diabetes epidemiology as a tool to trigger diabetes research and care

1999

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Section: Screening For Diabetesmentioning

confidence: 99%

Section: Screening For Diabetesmentioning

confidence: 99%

Diabetes epidemiology as a tool to trigger diabetes research and care

1999

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“…The potential of oral administration of autoantigens or their derivatives for the amelioration of autoimmune diseases was first demonstrated in a model of collagen-induced arthritis in rats that was suppressed by oral administration of type II collagen (2,3). Since then, many groups have demonstrated suppression of autoimmune responses in a variety of animal models, which led to a series of clinical trials in humans suffering from multiple sclerosis (4), rheumatoid arthritis (5), uveitis (6), and type I diabetes (7). Three basic mechanisms have been suggested to contribute to mucosal Ag-driven tolerance: clonal deletion, clonal anergy, and active suppression.…”

mentioning

confidence: 99%

Role of Tolerogen Conformation in Induction of Oral Tolerance in Experimental Autoimmune Myasthenia Gravis

Barchan

Souroujon

et al. 2000

The Journal of Immunology

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We recently demonstrated that oral or nasal administration of recombinant fragments of the acetylcholine receptor (AChR) prevents the induction of experimental autoimmune myasthenia gravis (EAMG) and suppresses ongoing EAMG in rats. We have now studied the role of spatial conformation of these recombinant fragments in determining their tolerogenicity. Two fragments corresponding to the extracellular domain of the human AChR α-subunit and differing in conformation were tested: Hα1–205 expressed with no fusion partner and Hα1–210 fused to thioredoxin (Trx), and designated Trx-Hα1–210. The conformational similarity of the fragments to intact AChR was assessed by their reactivity with α-bungarotoxin and with anti-AChR mAbs, specific for conformation-dependent epitopes. Oral administration of the more native fragment, Trx-Hα1–210, at the acute phase of disease led to exacerbation of EAMG, accompanied by an elevation of AChR-specific humoral and cellular reactivity, increased levels of Th1-type cytokines (IL-2, IL-12), decreased levels of Th2 (IL-10)- or Th3 (TGF-β)-type cytokines, and higher expression of costimulatory factors (CD28, CTLA4, B7-1, B7-2, CD40L, and CD40). On the other hand, oral administration of the less native fragments Hα1–205 or denatured Trx-Hα1–210 suppressed ongoing EAMG and led to opposite changes in the immunological parameters. It thus seems that native conformation of AChR-derived fragments renders them immunogenic and immunopathogenic and therefore not suitable for treatment of myasthenia gravis. Conformation of tolerogens should therefore be given careful attention when considering oral tolerance for treatment of autoimmune diseases.

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“…Trials are currently underway to study prevention strategies in those individuals at risk for developing diabetes [91,92]. In the Diabetes Prevention Trial-Type I (DPT-1), patients judged by their family history to be at an intermediate risk for developing diabetes were randomized to receive either oral insulin or placebo [91].…”

Section: Insulin Dependent Diabetes Mellitus Trialsmentioning

confidence: 99%

“…In the Diabetes Prevention Trial-Type I (DPT-1), patients judged by their family history to be at an intermediate risk for developing diabetes were randomized to receive either oral insulin or placebo [91]. At the completion of this trial, it will be clearer whether oral tolerization strategies can be used early on in the course of autoimmunity.…”

Section: Insulin Dependent Diabetes Mellitus Trialsmentioning

confidence: 99%

Oral tolerance in the treatment of inflammatory autoimmune diseases

Wardrop

1999

Inflamm. res.

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Oral tolerance refers to the oral administration of protein antigens, which induces a state of systemic nonresponsiveness specific for the fed antigen. This method of inducing immune non-responsiveness has been applied to the prevention and treatment of experimental animal models of autoimmune disease. Extensive research in this area over the past ten years has led to the conclusion that two mechanisms are operative in the mediation of oral tolerance--active suppression and clonal anergy/deletion. A number of factors have been identified that determine which mechanism of tolerance is operative--antigen dose, antigen form, and the timing of antigen administration. Work from these animal models has recently been extended into human clinical trials of multiple sclerosis, rheumatoid arthritis, diabetes, uveitis, and allergy, with differing degrees of success. In this review, a discussion is provided of the animal model systems where oral tolerance has been applied and the clinical trials where an oral tolerization approach has been attempted. Moreover, recent mechanistic studies are reviewed and a model proposed for the induction of oral tolerance.

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Prevention of insulin-dependent diabetes mellitus: an overview of three trials

Cited by 18 publications

References 8 publications

Diabetes epidemiology as a tool to trigger diabetes research and care

Diabetes epidemiology as a tool to trigger diabetes research and care

Role of Tolerogen Conformation in Induction of Oral Tolerance in Experimental Autoimmune Myasthenia Gravis

Oral tolerance in the treatment of inflammatory autoimmune diseases

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