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

Abstract

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

Cytokine profile and insulin antibody IgG subclasses in patients with recent onset Type 1 diabetes treated with oral insulin

“…This observation is in agreement with a previous study which showed that oral insulin administration is associated with lower levels of IgG1-IA after 3 months of treatment [15]. Conversely, subcutaneous insulin administration has been shown to induce high levels of IgG1-IA and a Th2-associated IgG4 response against insulin after 12 months of treatment [21].…”

Early epitope- and isotype-specific humoral immune responses to GAD65 in young children with genetic susceptibility to type 1 diabetes

“…The administration of intranasal insulin has not been observed to affect first-phase insulin response and the levels of GAD65Ab in autoantibody-positive subjects at risk for T1D (35). Similarly, the initiation of exogenous insulin treatment in patients with newly diagnosed T1D has not been observed to induce any isotype-specific responses to GAD65 although induction of an Ig4 response to insulin was observed (36). This indicates that intranasal insulin treatment hardly had any impact on the present observations, and consistently, no immediate change was observed in isotype-or epitope-specific responses after the initiation of the intervention trial in the present study.…”

Type 1A Diabetes Induced by Infection and Immunization

“…It has been reported that insulin immunization in animal models drives a Th2 dominated phenotype and induces Th2-like antibody subclass responses to insulin [58]. Antigen induction of a Th2 regulatory response may also occur in man as illustrated in a recent study which reported that the antibody subclass of the insulin autoantibodies in insulin-treated patients was consistent with enhancement of Th2 autoimmunity [65].…”