The human cellular immune response to insulin: a study in unexposed control subjects and type I diabetic patients on acute and chronic treatment.
Using a cellular cytotoxicity assay, we have investigated the antigenicity of pharmaceutical insulins and of highly purified insulin constituents (unformulated monocomponent (MC) insulin, insulin B-component and C-peptide) in control, insulin naive, subjects and in three groups of type I diabetic patients. These were: Group 1, newly diagnosed patients receiving either porcine or bovine MC insulins for less than one week; Group 2, established patients receiving porcine or bovine MC insulin for 2-6 years; Group 3, established patients receiving conventional bovine insulin for 2-6 years, and tested within two weeks of switching to either porcine or bovine MC insulins. In control subjects, there was a higher incidence of cytotoxic reactions with beef (72%) than with porcine (33%) pharmaceutical preparations (p less than 0.01) but there was a similar incidence of reactions with the purified beef and pork constituents. All patients, except those Group 3 patients receiving bovine MC insulins, had a significantly increased incidence of aggregate reactions to the spectrum of antigens. In porcine treated patients, there was an increase in the incidence of reactions to pharmaceutical preparations in Group 1 (p less than 0.05) and Group 3 (p less than 0.001), but this was absent from each of the bovine treated groups. All patient groups showed significant increases in the incidence of reactions against insulin constituents of their therapeutic analog. In Groups 1 and 2, but not 3, there was significant analog cross reactivity. We deduce that the reactivity seen in control subjects is principally directed against unidentified formulation constituents of bovine pharmaceutical preparations. Patients on both acute and chronic therapy with insulin show T-cell sensitization to MC insulin and its components. Chronic therapy with conventional bovine insulin induces tolerogenesis, but this is reversed on exposure to a fresh insulin analog.
D000328:Adult; D002096:C-Peptide / Q000276:immunology; D003601:Cytotoxicity Tests, Immunologic; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy / Q000276:immunology*; D005260:Female; D006801:Humans; D007328:Insulin / Q000276:immunology* / Q000627:therapeutic use; D007330:Insulin Antibodies / Q000276:immunology*; D008297:Male; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
D002096:C-Peptide; D007328:Insulin; D007330:Insulin Antibodies