Immunology of IDDM

Insulin-dependent diabetes mellitus (IDDM) is at the forefront as a paradigm for research on polygenic disorders and on the early diagnosis, prediction and prevention of autoimmune disease. There is growing anticipation that knowledge of the genetic susceptibility and processes of beta-cell destruction, gained over the past two decades, herald an era of targeted therapy for the prevention of IDDM; and without prevention there can be no cure. The genetic dissection of IDDM and the molecular immunology of IDDM are converging on the functional mechanisms by which IDDM susceptibility gene products contribute to disease pathogenesis. This is illustrated by the role of the HLA-DQ8 (3.2) antigen-presenting molecule and its counterpart, I-A g7 , in the NOD mouse model of IDDM. Increasing evidence supports the determinant selection model for MHC susceptibility molecules such as HLA-DQ8 (or protective molecules such as DQ6) in which these molecules bind specific peptides that regulate T-cell immunity against pancreatic beta-cells. The appeal of this model is that it identifies not only pathogenic T-cell epitopes but peptides that have potential as immunotherapeutic agents. Already, peptides restricted by I-A g7 have been shown to be immunoregulatory when administered, e. g. transmucosally, in the NOD mouse. The functional consequence of T-cell receptor recognition of peptide-MHC complexes, i. e. the nature of the Tcell response, is determined in the first instance by the peptide antigen itself and the avidity of its interaction. Given the tremendous advances in the immunology and genetics of IDDM, and the techniques now at our disposal, it is appropriate to further strengthen the marriage between basic research and clinical application.