GAD Treatment and Insulin Secretion in Recent-Onset Type 1 Diabetes

Ludvigsson, Johnny; Faresjö, Maria; Hjorth, Maria; Axelsson, Stina; Chéramy, Mikael; Pihl, Mikael; Vaarala, Outi; Forsander, Gun; Ivarsson, Sten; Johansson, Christer; Lindh, Agne; Nilsson, Nils-Östen; Åman, Jan; Örtqvist, Eva; Zerhouni, Peter; Casas, Rosaura

doi:10.1056/nejmoa0804328

Cited by 465 publications

(430 citation statements)

References 28 publications

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“…A dose-finding study in Latent Autoimmune Diabetes in Adults (LADA) patients supported the clinical effect and safety of subcutaneous administration of 20 µg alum-formulated recombinant human GAD 65 (GADalum) [13], and the 5-year follow up suggests a persistent effect [14]. We have conducted a phase II clinical trial, where we showed that two injections of 20 µg GAD-alum contributes to the preservation of residual insulin secretion in children with recent onset type 1 diabetes [15].…”

Section: Introductionmentioning

confidence: 91%

GAD-alum treatment in patients with type 1 diabetes and the subsequent effect on GADA IgG subclass distribution, GAD65 enzyme activity and humoral response

Chéramy

Skoglund

Johansson

et al. 2010

Clinical Immunology

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, GAD-alum treatment in patients with type 1 diabetes and the subsequent effect on GADA IgG subclass distribution, GAD (65) AbstractWe have previously shown that two injections of 20 μg GAD-alum to recent onset type 1 diabetic children induced GADA levels in parallel to preservation of insulin secretion. Here we investigated if boosted GADA induced changes in IgG1, 2, 3 and 4 subclass distributions or affected GAD 65 enzyme activity. We further studied the specific effect of GAD-alum through analyses of IA-2A, tetanus toxoid and total IgE antibodies. Serum from children receiving GAD-alum or placebo was collected pre-treatment and after 3, 9, 15 and 21 months.At 3 month a reduced percentage of IgG1 and increased IgG3/IgG4 were detected in GADalum treated. Further, IA-2A, IgE and tetanus toxoid antibodies, as well as GAD 65 enzyme activity, were unaffected confirming the specific effect of treatment. In the GAD-alum group, higher pre-treatment GADA were associated to more pronounced C-peptide preservation. The induced IgG3/IgG4 and reduced IgG1 suggest a Th2 deviation of the immune response.

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Section: Introductionmentioning

confidence: 91%

GAD-alum treatment in patients with type 1 diabetes and the subsequent effect on GADA IgG subclass distribution, GAD65 enzyme activity and humoral response

Chéramy

Skoglund

Johansson

et al. 2010

Clinical Immunology

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“…While insulin autoimmunity is affecting the young, GAD65 autoimmunity is less sensitive to age. Alum-formulated recombinant human GAD65 tested in Phase II and III clinical trials were found to be safe [38][39][40] . The immunomodulating effect seemed to include the induction of Treg cells 16,38 and the residual beta-cell function in newly diagnosed T1D patients.…”

Section: Glutamic Acid Decarboxylase (Gad65)mentioning

confidence: 99%

“…GAD-alum tested in Phase II clinical trials with some effect on preserving residual cpeptide 39,40 was tested in an additional phase II trial with a dose-regiment that differed from previous trials 53 . Two or three doses of subcutaneous GAD-alum across 4-12 weeks did not alter the c-peptide disappearance rate during 12 month in newly diagnosed T1D patients (NCT00529399).…”

Section: Gad-alummentioning

confidence: 99%

“…Whether a future trial is prevention or intervention safety and long-term effects will have to be a major concern. So far, the safety profile in trials with insulin 22,36 and GAD65 38,40 autoantigen immunomodulation has been high. The different approaches of autoantigen administration have revealed effects on secondary end-point measures such as increased numbers of Treg cells.…”

Section: E Future Directionsmentioning

confidence: 99%

“…The different approaches of autoantigen administration have revealed effects on secondary end-point measures such as increased numbers of Treg cells. Although β-cell function has not been fully preserved 40 and reproducible 53,54 these high safety studies makes it possible to design trials to evaluate dose and exposure dependent parameters. Recent advances in flow cytometry, immunogenetics in combination with β-cell function tests such as the MMTT should make it possible to dissect the impact of autoantigen immunomodulation on the immune response in relation to β-cell function.…”

Section: E Future Directionsmentioning

confidence: 99%

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Immune therapy in type 1 diabetes mellitus

Lernmark

Larsson

2013

Nat Rev Endocrinol

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(200 words) Type 1 diabetes mellitus (T1D) is an autoimmune disorder directed against the pancreatic islet β cells. The genetic risk for the disease is linked to HLA-DQ genotypes and unknown environmental triggers. In most countries, only 10-15% of newly diagnosed T1D children or young adults have a first degree relative with the disease. Autoantibodies against insulin, GAD65, IA-2 or ZnT8 transporter mark islet autoimmunity. These islet autoantibodies may develop already at 1-2 years of age. Immune therapy in T1D is approached at three stages. Primary prevention is treatment of subjects at increased genetic risk. The TRIGR trial is testing if hydrolyzed casein milk formula may reduce T1D in genetically predisposed infants. Secondary prevention is in subjects with persistent islet autoantibodies. On-going trials are either non-autoantigen (BCG, CD3 monoclonal antibodies) or autoantigen (oral and nasal insulin or Alum-formulated GAD65) specific. Intervention at diabetes onset include non-autoantigen (CD3 monoclonal antibodies, IL-2 receptor antibodies, Il-1b receptor inhibitor, Il-1b antibodies, BCG, ATG, DiaPep277) and autoantigen (proinsulin peptides) specific therapy. Although preserved beta-cell function long term has been difficult to achieve in many prior studies, considerable progress is being made through controlled clinical trials and animal investigations to uncover mechanisms of beta-cell destruction. Novel therapies that would prevent islet autoimmunity or halt progressive beta-cell destruction need to be designed.

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Effect of Cholecalciferol as Adjunctive Therapy With Insulin on Protective Immunologic Profile and Decline of Residual β-Cell Function in New-Onset Type 1 Diabetes Mellitus

Gabbay¹,

Sato²,

Finazzo³

et al. 2012

Arch Pediatr Adolesc Med

123

118

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GAD Treatment and Insulin Secretion in Recent-Onset Type 1 Diabetes

Abstract: GAD-alum may contribute to the preservation of residual insulin secretion in patients with recent-onset type 1 diabetes, although it did not change the insulin requirement. (ClinicalTrials.gov number, NCT00435981.)

Cited by 465 publications

References 28 publications

GAD-alum treatment in patients with type 1 diabetes and the subsequent effect on GADA IgG subclass distribution, GAD65 enzyme activity and humoral response

GAD-alum treatment in patients with type 1 diabetes and the subsequent effect on GADA IgG subclass distribution, GAD65 enzyme activity and humoral response

Immune therapy in type 1 diabetes mellitus

Effect of Cholecalciferol as Adjunctive Therapy With Insulin on Protective Immunologic Profile and Decline of Residual β-Cell Function in New-Onset Type 1 Diabetes Mellitus

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