Follow-up of cyclosporin A treatment in Type 1 (insulin-dependent) diabetes mellitus: lack of long-term effects

Martin, St.; Schernthaner, Guntram; Nerup, Jørn; Gries, F. A.; Koivisto, Veikko A.; Dupré, J.; Standl, Eberhard; Hamet, Pavel; McArthur, Robert G.; Tan, Meng H.; Dawson, Keith; Mehta, Adi; Vliet, Stephan van; Graffenried, B. von; Stiller, C. R.; Kolb, Hubert

doi:10.1007/bf00403182

Cited by 68 publications

(25 citation statements)

References 9 publications

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“…The fact that all antibody markers remained positive under immune intervention also supports the assumption that autoimmunity towards beta cells continues. Similar findings have been reported under immunosuppression with cyclosporin after the onset of overt Type I diabetes [12].…”

Section: Discussionsupporting

confidence: 88%

Delay of Type I diabetes in high risk, first degree relatives by parenteral antigen administration: the Schwabing Insulin Prophylaxis Pilot Trial

et al. 1998

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Type 1 diabetes is an autoimmune disorder in which the destruction of insulin-producing beta-cells can be detected years before the clinical manifestation of the disease [1]. Selective autoantibody assays and metabolic testing can now identify first degree relatives of Type I diabetic patients, in whom the risk of diabetes is over 80 % at 5 years [2,3]. The ability to identify subjects at risk makes the exploration of immune intervention strategies to halt or even prevent betacell destruction a major goal. Growing evidence in animal models of Type I diabetes mellitus suggests Diabetologia (1998) Summary The Schwabing Insulin Prophylaxis Trial is a randomised, controlled pilot study designed to examine whether insulin therapy can delay or prevent the clinical onset of Type I diabetes in high risk first degree relatives of people with the disease. First degree relatives of patients with Type I diabetes, who were aged 4 years or more, had an islet cell antibody (ICA) value more than 20 Junevile Diabetes Foundation Units (JDF-U), a reduced first phase insulin response (FPI) to an i. v. glucose tolerance test less than the 5th centile, and a normal oral glucose tolerance test were eligible for the trial. Between January 1989 and October 1995, 1736 relatives of patients with Type I diabetes were screened for ICA. We identified 64 cases (3.7 %) with ICA values more than 20 JDF-U. Of ICA positive relatives, 17 (27 %) had a low FPI and were eligible for enrolment. Of these 14 agreed to participate, of whom 7 were randomised to the treatment group and 7 to the control group. In the treatment group, human insulin was administered i. v. by continuous infusion for 7 days, followed by daily s. c. injections for 6 months. Intravenous insulin infusions were repeated every 12 months. In the treatment group 3 of the 7 individuals (follow-up from time of eligibility: 2.3 to 7.1 years) and in the control group 6 of the 7 untreated individuals (1.7 to 7.1 years) developed clinical diabetes. Life table analysis showed that clinical onset of Type I diabetes was delayed in insulin-treated subjects compared with control subjects (means ± SEM diabetes-free survival: 5.0 ± 0.9 years vs 2.3 ± 0.7 years, p < 0.03). Insulin levels after i. v. glucose increased in the first year of intervention therapy. Titres of ICA, and antibodies to glutamic acid decarboxylase, and tyrosine phosphatase-like protein IA2 remained unchanged. These data suggest that insulin prophylaxis can delay the onset of overt diabetes in high risk relatives. This is encouraging in view of 1) the continuing American Diabetes Prevention Trial, which is currently testing the effect of parenteral insulin in a large nation-wide study and 2) the initiation of pilot trials to determine whether new antigen-specific intervention is more effective in delaying the clinical onset of Type I diabetes. [Diabetologia (1998)

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Section: Discussionsupporting

confidence: 88%

Delay of Type I diabetes in high risk, first degree relatives by parenteral antigen administration: the Schwabing Insulin Prophylaxis Pilot Trial

et al. 1998

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“…In this study, we measured IgG subclass responses to insulin to test the hypothesis that immunization with antigens will induce Th2 immunity to specific antigens and induce spreading to Th2 immunity to other islet autoantigens. We investigated the course of the humoral immune response to insulin by determining total and specific IgG antibody subclass titers in the following groups: 1) patients treated with intravenous and subcutaneous insulin or with subcutaneous insulin alone from diabetes onset; 2) a group of newly diagnosed patients who were treated with cyclosporin A (CsA) or placebo and subcutaneous insulin for 12 months in the European-Canadian Cyclosporin Trial (16,17); and 3) prediabetic first-degree rel-atives treated with intravenous and subcutaneous insulin in the Schwabing Insulin Prophylaxis (SIP) pilot intervention trial (9). Changes in the subclass of antibodies to GAD and I A-2 after insulin therapy were also investigated.…”

Section: Exposure To Exogenous Insulin Promotes Igg1 and The T-helpermentioning

confidence: 99%

“…Patients with newly diagnosed type 1 diabetes treated with CsA plus i n s u l i n . Ten patients with newly diagnosed type 1 diabetes who were randomized into the Canadian-European Cyclosporin Trial by our participating center in Munich were analyzed for this study (17). Five patients (median age 18 years, range 17-28) were randomized into the CsA arm and treated with an initial daily dose of 10 mg CsA/kg plus subcutaneous insulin given orally in divided doses at 12-h intervals.…”

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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“…Based on results from pilot studies [32,33], two randomized phase II placebo-controlled studies were conducted [34,35]. Based on these studies, it was concluded that treatment with CsA had no long-lasting effect on the course of T1D, persisting upon removal of compound administration [34,36]. The need for chronic drug administration, the potential renal and pancreatic β-cell toxicity, and the cost for the drug led to the consensus that the risks outweighed the benefits, and the approach was dropped.…”

Section: Cyclosporin Amentioning

confidence: 99%

Immunotherapy in Autoimmune Type 1 Diabetes

Weigmann

Franke²,

Daniel³

2012

Rev Diabet Stud

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■ AbstractType 1 diabetes (T1D) is a chronic autoimmune disease affecting millions of people worldwide. The disease is characterized by the loss of self-tolerance to the insulin-producing β-cells in the pancreas, the destruction of β-cells, and finally the development of chronic hyperglycemia at diagnosis of T1D. Its incidence and prevalence are rising dramatically, highlighting the need for immunotherapeutic strategies able to prevent or treat the disease in a safe and specific manner. Immunotherapeutic strategies are being developed, and aim to restore immunological self-tolerance, thereby limiting unwanted immunity and β-cell destruction. Foxp3 + regulatory T (Treg) cells exert essential functions to maintain and restore immunological self-tolerance. The identification of the transcription factor Foxp3 as the specification factor for the Treg cell lineage facilitated our understanding in the biology of Treg generation and function. This review highlights the current understanding of immunotherapeutic approaches as preventative and curative measures for autoimmune T1D. It includes an overview on early immunointervention studies, which made use of general immunosuppressive agents such as cyclosporin A, followed by a discussion on newly emerging clinical trials. Besides non-antigenspecific therapies, particular attention is given to antigenspecific generation of Foxp3 + Treg cells and their potential use to limit autoimmunity such as T1D.

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Follow-up of cyclosporin A treatment in Type 1 (insulin-dependent) diabetes mellitus: lack of long-term effects

Cited by 68 publications

References 9 publications

Delay of Type I diabetes in high risk, first degree relatives by parenteral antigen administration: the Schwabing Insulin Prophylaxis Pilot Trial

Delay of Type I diabetes in high risk, first degree relatives by parenteral antigen administration: the Schwabing Insulin Prophylaxis Pilot Trial

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

Immunotherapy in Autoimmune Type 1 Diabetes

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