ALTERED IMMUNE-RESPONSE TO INSULIN IN NEWLY-DIAGNOSED COMPARED TO INSULIN-TREATED DIABETIC-PATIENTS AND HEALTHY CONTROL SUBJECTS

Insulin-dependent diabetes mellitus (IDDM) is the result of a T-cell m ediated autoimmune beta-cell destruction,which is accompanied by autoa ntibodies. We analysed the cellular and humoral immune response to ins ulin and insulin peptides in patients with recent-onset IDDM, IDDM pat ients treated with insulin, non-diabetic first degree relatives and un related control subjects. There were no differences in T-cell reactivi ty to whole insulin or insulin peptides in general between age-matched groups of IDDM patients, relatives or healthy control subjects. In co ntrast to investigations in NOD mice, no immunodominant or disease-spe cific insulin peptide could be identified. Surprisingly, a positive co rrelation of T-cell responses to insulin with age was noted (p < 0.005 ). This resulted in an inverse relation of insulin autoantibodies (IAA ) and insulin reactive T-cells (p < 0.001) together with the well-desc ribed negative correlation of IAA with age. Interestingly, insulin-tre ated patients differed from age-matched recent-onset IDDM patients: fi rst, simultaneous immune recognition of insulin with T-cells and IAA w as only seen in patients treated for 6 months with insulin; second, in sulin-treated patients rarely responded to whole insulin; third, they displayed less determinant spreading, and finally, recognition of mult iple insulin peptides was not accompanied by crossreactivity to whole insulin. These distinct observations in insulin-treated IDDM patients, together with the inverse correlation between humoral and cellular re sponses to insulin, may result from activation or modulation of differ ent T-cell subsets, and may be of relevance to insulin therapy trials, in which selective activation of non-destructive T-cell subsets may b e a key to successful intervention.