Perspectives in Diabetes Immunoregulatory and Cytokine Imbalances in the Pathogenesis of IDDM

The autoimmune response that leads to destruction of pancreatic islet p-cells and insulin-dependent diabetes mellitus (IDDM) has a genetic basis; however, environmental factors can exert profound modulating effects on the genetic predisposition to this autoimmune response. Recent studies in animal models for human IDDM, the genetically diabetes-prone NOD mouse and BB rat, have revealed that microbial agents-including certain viruses and extracts of bacteria, fungi, and mycobacteria-often have a protective action against diabetes development. Many of' these microbial preparations are immune adjuvants, which are agents that stimulate the immune system. The protective effects of these agents against diabetes appear to involve perturbations in the production of cytokines, which are polypeptides produced by and acting on cells of the immune system. Thus, recent studies in NOD mice suggest that the islet P-cell-directed autoimn~une response may be mediated by a T-helper 1 (Thl) subset of T-cells producing the cytokines interleukin-2 (IL-2) and interferon-?. These studies also suggest that the diabetes-protective effects of administering microbial agents, adjuvants, and a P-cell autoantigen (GAD65 [glutamic acid decarboxylase]) may result from activation of a Th2 subset of T-cells that produce the cytokines IL-4 and IL-10 and consequently downregulate the Thl-cell-mediated autoimmune response. The clinical implication of these findings is that the autoimmune response leading to islet P-cell destruction and IDDM may be amenable to prevention or suppression by therapeutic interventions aimed at stimulating the host's own immunoregulatory mechanisms. Diabetes 43:613-621, 1994