The effect of immunosuppression on the humoral immune response to islet autoantigens and exogenously administered insulin and the predictive value of islet cell cytoplasmic antibodies (ICAs), insulin antibodies (IAs), and HLA-DR phenotype for remission during immunosuppression were studied in a prospective randomized double-blind trial of cyclosporin administration in 98 newly diagnosed insulin-dependent diabetes mellitus (IDDM) patients. HLA-DR phenotype and glycosylated hemoglobin were determined at study entry, and insulin requirement, glucagon-stimulated C-peptide, ICAs, and IAs were measured at entry and after 1, 3, 6, 9, and 12 mo of follow-up. Cyclosporin therapy caused significant suppression of the prevalence and serum concentrations of ICAs and lAs. Cyclosporin-treated IDDM patients ICA+ at study entry had higher levels of stimulated C-peptide after 1 mo of study, but the increased (β-cell function was not associated with a higher frequency of insulin-free remission at 1 mo. ICA and IA status at entry did not predict cyclosporininduced remission as assessed by the prevalence of insulin-free remission or β-cell function at 3–12 mo of study, and significant decrements in the titers or total disappearance of ICAs were not associated with an increased prevalence or duration of non-insulinrequiring remission or higher stimulated C-peptide values. There was no correlation between the serum levels of ICAs and lAs at entry and β-cell function at 12 mo of follow-up. Although patients who were HLADR3/X seemed to respond better to cyclosporin therapy at 6 mo than patients who were HLA-DR3/4 or -DR4/X when analyzed cross-sectionally, a split-plot analysis of variance with time as the split-plot factor showed that the HLA-DR phenotype failed to identify patients with an overall better response to cyclosporin therapy. These data indicate that, although cyclosporin therapy inhibits the humoral immune response to islet components and exogenous insulin, significant decrements in ICA titers are not useful in monitoring efficacy of immunosuppression with cyclosporin, and the determination of ICA and IA status and immune response phenotype at diagnosis is of no predictive value for remission in selecting recent-onset IDDM patients for cyclosporin immunointervention.

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