Immunopathogenesis and immunotherapy of type 1 diabetes

Research in recent years has elucidated more clearly the genetic and immunopathogenic basis as well as the natural history of Type 1 diabetes mellitus. The development of Type 1 diabetes can be conceptually divided into stages, beginning in part with a human leukocyte antigen (HLA)-restricted genetic susceptibility. In some genetically susceptible subjects, a triggering event activates both cellular and humoral autoimmunity. Glucose-stimulated insulin secretion and beta cell mass diminish as anti-islet autoimmunity progresses. This process culminates in overt diabetes when only residual beta cell mass (estimated to be less than 10%) remains. Complete beta cell destruction follows within months to years of diagnosis. Most attempts at interrupting beta cell destruction have taken the form of broad immunosuppressive therapy begun at diagnosis when beta cell destruction is nearly complete. Greater understanding of early immune mediators and refinement of techniques to identify subjects at risk for Type 1 diabetes have set the stage for more specific immunomodulation targeted earlier in the course of the disease. We will review these recent advances in understanding the immunopathogenesis of Type 1 diabetes as they pertain to current and future trials of immunotherapy.