Approaches to type 1 diabetes prevention by intervention in cytokine immunoregulatory circuits

Abstract

Type 1 (insulin-dependent) diabetes mellitus, like other organ specific autoimmune diseases, results from a disorder of immunoregulation. T cells specific for pancreatic islet β cell constituents (autoantigens) exist normally but are restrained by regulatory mechanisms (self-tolerant state). When regulation fails, β cell-specific autoreactive T cells become activated and expand clonally. Current evidence indicates that islet β cell-specific autoreactive T cells belong to a T helper 1 (Th1) subset, and these Th1 cells and their characteristic cytokine products, IFNγ and IL-2, are believed to cause islet inflammation (insulitis) and β cell destruction. Immune-mediated destruction of β cells precedes hyperglycemia and clinical symptoms by many years because these become apparent only when most of the insulin-secreting β cells have been destroyed. Therefore, several approaches are being tested or are under consideration for clinical trials to prevent or arrest complete autoimmune destruction of islet β cells and insulin-dependent diabetes. Approaches that attempt to correct underlying immunoregulatory defects in autoimmune diabetes include interventions aimed at i) deleting β cell autoreactive Th1 cells and cytokines (IFNγ and IL-2) and/or ii) increasing regulatory Th2 cells and/or Th3 cells and their cytokine products (IL-4, IL-10 and TGFβ1).