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 mediated autoimmune beta-cell destruction, which is accompanied by autoantibodies. We analysed the cellular and humoral immune response to insulin and insulin peptides in patients with recent-onset IDDM, IDDM patients treated with insulin, non-diabetic first degree relatives and unrelated control subjects. There were no differences in T-cell reactivity to whole insulin or insulin peptides in general between age-matched groups of IDDM patients, relatives or healthy control subjects. In contrast to investigations in NOD mice, no immunodominant or disease-specific insulin peptide could be identified. Surprisingly, a positive correlation of T-cell responses to insulin with age was noticed (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-described negative correlation of IAA with age. Interestingly, insulin-treated patients differed from age-matched recent-onset IDDM patients: first, simultaneous immune recognition of insulin with T-cells and IAA was only seen in patients treated for 6 months with insulin; second, insulin-treated patients rarely responded to whole insulin; third, they displayed less determinant spreading, and finally, recognition of multiple 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 responses to insulin, may result from activation or modulation of different T-cell subsets, and may be of relevance to insulin therapy trials, in which selective activation of non-destructive T-cell subsets may be a key to successful intervention.
Schloot
N C
NC
Barbara Davis Center for Childhood Diabetes, University of Colorado, Denver, USA.
Roep
B O
BO
Wegmann
D
D
Yu
L
L
Chase
H P
HP
Wang
T
T
Eisenbarth
G S
GS
D000293:Adolescent; D000328:Adult; D000483:Alleles; D000595:Amino Acid Sequence; D000818:Animals; D001323:Autoantibodies / Q000097:blood*; D002478:Cells, Cultured; D002648:Child; D002675:Child, Preschool; D017124:Conserved Sequence; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy* / Q000235:genetics / Q000276:immunology*; D005190:Family; D005260:Female; D006683:HLA-DQ Antigens / Q000032:analysis / Q000235:genetics; D059848:HLA-DQ alpha-Chains; D059866:HLA-DQ beta-Chains; D006801:Humans; D007328:Insulin / Q000276:immunology* / Q000494:pharmacology / Q000627:therapeutic use; D007330:Insulin Antibodies / Q000097:blood*; D007515:Islets of Langerhans / Q000276:immunology; D008213:Lymphocyte Activation; D008297:Male; D051379:Mice; D016688:Mice, Inbred NOD; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry; D011994:Recombinant Proteins / Q000276:immunology / Q000494:pharmacology / Q000627:therapeutic use; D012016:Reference Values; D018570:Risk Assessment; D013601:T-Lymphocytes / Q000276:immunology; D013997:Time Factors
D001323:Autoantibodies; D006683:HLA-DQ Antigens; D059848:HLA-DQ alpha-Chains; D059866:HLA-DQ beta-Chains; C069050:HLA-DQA1 antigen; C069051:HLA-DQB1 antigen; D007328:Insulin; D007330:Insulin Antibodies; D010446:Peptide Fragments; D011994:Recombinant Proteins; C024211:islet cell antibody