Disappearance and Reappearance of Islet Cell Cytoplasmic Antibodies in Cyclosporin-Treated Insulin-Dependent Diabetics

Mandrup-Poulsen, Thomas; Stiller, C. R.; Billè, Giuseppe; Martell, R.; Keown, P. A.; Rodger, N. W.; Graffenried, B. von; Nerup, J.; Marner, B.; Heinrichs, Daniel; Dupré, J.; Jenner, M.; Wolfe, B. M.; Binder, Christian

doi:10.1016/s0140-6736(85)92143-9

Cited by 60 publications

(26 citation statements)

References 27 publications

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“…Other untoward effects such as abdominal discomfort, nausea, vomiting, diarrhoea and infections, or off-target effects, may also explain, at least in part, the metabolic effects of ciclosporin on diabetes-independent of its immunosuppressive effects. The lack of a temporal correlation between changes in islet cell antibodies and changes in C-peptide levels are also in line with this supposition [11]. Indeed, this observation has given rise to the hypothesis that the generation of autoantibodies in type 1 diabetes may be a secondary event triggered by a primary islet-destructive process.…”

supporting

confidence: 59%

What is the role of autoimmunity in type 1 diabetes? A clinical perspective

2014

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Despite tremendous research efforts, type 1 diabetes is one of the few remaining autoimmune diseases without any approved immunological treatment. This observation compels us to reconsider the role of autoimmunity in the pathogenesis of this disease. In this commentary, we will review solely human data in an attempt to appreciate, in an unbiased manner, the importance and relevance of the immunological alterations in patients with type 1 diabetes. The aim of this paper is to generate reflection on this topic, rather than a controversy.

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supporting

confidence: 59%

What is the role of autoimmunity in type 1 diabetes? A clinical perspective

2014

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“…S a mples were analyzed from 29 patients with type 1 diabetes treated with either high-dose intravenous insulin infusion for 1-2 weeks followed by subcutaneous insulin therapy (n = 14) or subcutaneous insulin therapy alone (n = 15) (11). Those patients who were treated with intravenous plus subcutaneous insulin included 6 children (median age 7 years, range 2-12) and 8 adults (median age 29 years, range [19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36]. Of the patients treated with subcutaneous insulin alone, 6 were children (median age 11 years, range 3-17) and 9 were adults (median age 31 years, range 24-37).…”

Section: S U B J E C T Smentioning

confidence: 99%

Exposure to exogenous insulin promotes IgG1 and the T-helper 2-associated IgG4 responses to insulin but not to other islet autoantigens.

et al. 2000

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Insulin immunization in animal models induces T-h e l p e r (Th) 2-like antibody subclass responses to insulin and other -cell antigens. The aim of this study was to d e t e rmine whether exposure to insulin in humans resulted in a similar subclass bias of the humoral immune response. Levels of IgG subclass antibodies to insulin (IAs), GAD, and IA-2 were measured before and after treatment w i t h insulin in the following groups of patients: 29 patients with newly diagnosed type 1 diabetes treated with intravenous and/or subcutaneous insulin; 10 newly diagnosed patients randomized to cyclosporin A (CsA) or placebo plus subcutaneous insulin for 12 months; and 14 islet cell antibody-positive relatives receiving either intravenous and subcutaneous insulin prophylaxis or no treatment. At the onset of diabetes, the major subclass distributions of insulin autoantibodies (IAAs) were IgG1 and, to a lesser extent, IgG4. After insulin treatment in the 29 new-onset patients, IAs were initially of the IgG1 subclass. IgG4-IAs appeared later, but at 12 months, they were at higher levels than IgG1-IAs in 11 patients. Responses were higher in children compared with adults and were higher in subjects with IAAs (P < 0.001). Insulin prophylaxis in relatives showed a similar profile, with a decline in levels of IgG1-IAs after cessation of daily subcutaneous insulin. Patients treated with CsA took longer to develop IAs and showed suppressed levels of IgG4-IAs; however, their levels of high-titer IgG1-IAs persistently rebounded after completion of CsA therapy. Despite the presence of IgG4-IAs in most insulin-treated patients and relatives, a shift to IgG4-anti-GAD or IgG4-IA-2 was not found for up to 3 years after the initiation of insulin t h e r a p y. While our findings need to be correlated with T-cell cytokine responses, we suggest that the strong IgG4-IA response in insulin-treated patients is consistent with an enhancement of Th2 immunity, but there is no evidence of subsequent spreading of potentially Th2-associated IgG4 responses to other autoantigens. D i a b e t e s 4 9 :9 1 8-925, 2000

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“…Genetic markers such as HLA or the presence of the immune markers islet cell antibodies (ICAs), insulin autoantibodies (IAAs), or GAD antibodies (GADAs) at onset of disease are not, by themselves, useful in predicting study outcome (2)(3)(4)(5)(6). Interestingly, cyclosporin was found to have different effects on the antibody responses to these target antigens after initiation of treatment.…”

mentioning

confidence: 99%

IA-2 Antibody-Negative Status Predicts Remission and Recovery of C-Peptide Levels in Type 1 Diabetic Patients Treated With Cyclosporin

Christie¹,

Mølvig

Hawkes³

et al. 2002

Diabetes Care

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OBJECTIVE—The use of cyclosporin in recent-onset type 1 diabetes has demonstrated the potential for immune intervention in the treatment and prevention of the disease. However, a proportion of patients failed to respond to cyclosporin treatment. Indicators of resistance to immune intervention would be valuable for the most effective use of such therapies in disease prevention. The aim of this study was to determine whether presence of IA-2 antibodies is such a marker. RESEARCH DESIGN AND METHODS—IA-2 antibodies were determined by radioligand binding assay in sera from patients recruited into the Canadian-European cyclosporin trial. Insulin dose requirements and glucagon-stimulated C-peptide secretion were analyzed in patients grouped according to IA-2 antibody status at entry. RESULTS—Cyclosporin treatment had no significant effect on frequency of IA-2 antibodies during the 1 year of treatment. Cyclosporin caused significant reduction in insulin requirements and significant increases in C-peptide secretion mainly in patients negative for IA-2 antibodies. Analysis of GAD antibodies in combination with antibodies to IA-2 indicated that the group most resistant to cyclosporin were IA-2 antibody positive, GAD antibody negative. CONCLUSIONS—The results demonstrate that IA-2 antibody analysis is valuable in identifying individuals for whom immunosuppressive treatment would be most effective.

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Disappearance and Reappearance of Islet Cell Cytoplasmic Antibodies in Cyclosporin-Treated Insulin-Dependent Diabetics

Cited by 60 publications

References 27 publications

What is the role of autoimmunity in type 1 diabetes? A clinical perspective

What is the role of autoimmunity in type 1 diabetes? A clinical perspective

Exposure to exogenous insulin promotes IgG1 and the T-helper 2-associated IgG4 responses to insulin but not to other islet autoantigens.

IA-2 Antibody-Negative Status Predicts Remission and Recovery of C-Peptide Levels in Type 1 Diabetic Patients Treated With Cyclosporin

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