There is heterogeneity within insulin-dependent diabetes meliitus (IDDM), and it has been suggested that the presence of the HLA-DR specificities DR3 and DR4 define two subsets of IDDM with clear differences in their immune response to therapeutic insulin. To test this hypothesis, we have prospectively studied the development of insulin binding antibody (IBA) in 54 subjects with newly diagnosed, classical childhood IDDM, determined seven binding constants of their IBA, and measured the presence or absence of pancreatic polypep-tide-binding antibodies after 1 yr of therapy with insulin. There were no relationships between insulin and pancreatic polypeptide antibodies and the DR3 or DR4 specificities whether these specificities were tested for alone or in combination, comparing the presence and absence of DR3 and DR4 and comparing DR3 with DR4, except that of the 33% of all subjects who developed antibodies binding pancreatic polypeptide by 1 yr, none possessed the DR3 specificity alone (P = 0.018). Thus, the hypothesis that the HLA-DR3 and -DR4 specificities are major determinants of IBA formation and, therefore, define important subsets of childhood IDDM in terms of immune response to therapeutic insulin is not substantiated by this study.

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