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

Insulin immunization in animal models induces T-helper (Th) 2-like antibody subclass responses to insulin and other beta-cell antigens. The aim of thi s study was to determine whether exposure to insulin in humans resulted in a similar subclass bias of the humoral immune response. Levels of IgG subcl ass antibodies to insulin (IAs), GAD, and IA-2 were measured before and aft er treatment with insulin in the following groups of patients: 29 patients with newly diagnosed type 1 diabetes treated with intravenous and/or subcut aneous insulin; 10 newly diagnosed patients randomized to cyclosporin A (Cs A) or placebo plus subcutaneous insulin for 12 months; and 14 islet cell an tibody-positive relatives receiving either intravenous and subcutaneous ins ulin prophylaxis or no treatment. At the onset of diabetes, the major subcl ass distributions of insulin autoantibodies (IAAs) were IgG1 and, to a less er 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 mo nths, they were at higher levels than IgG1-IAs in 11 patients. Responses we re higher in children compared with adults and were higher in subjects with IAAS (P < 0.001). Insulin prophylaxis in relatives showed a similar profil e, with a decline in levels of IgG1-IAs after cessation of daily subcutaneo us insulin. Patients treated with CsA took longer to develop IAs and showed suppressed levels of IgG4-IAs; however, their levels of high-titer IgG1-IA s persistently rebounded after completion of CsA therapy Despite the presen ce of IgG4-IAs in most insulin-treated patients and relatives, a shift to I gG4-anti-GAD or IgG4-IA-2 was not found for up to 3 years after the initiat ion of insulin therapy. While our findings need to be correlated with T-cel l cytokine responses, we suggest that. the strong IgG4-IA response in insul in-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.