CommentariesCytokines and Their Roles in Pancreatic Islet β-Cell Destruction and Insulin-Dependent Diabetes Mellitus
Section snippets
IDDM,
1 The Result of Disordered Regulation of Immune Responses
IDDM is a disease that results from destruction of the insulin-producing β-cells in the pancreatic islets of Langerhans. Current evidence favors the concept that β-cells are destroyed by an autoimmune response directed against certain β-cell constituents (autoantigens) [1]. This autoimmune response is thought to occur in genetically predisposed persons who possess certain “susceptibility” alleles and who lack other “protective” alleles of
Cytokine Regulation of Immune Responses
Th1 and Th2 cells are characterized by their distinct cytokine secretory products [4]. Th1 cells secrete IL-2, IFNγ, and TNFβ, whereas Th2 cells secrete IL-4 and IL-10. Also, other cytokines are produced by both Th1 and Th2 cells, and Th cell phenotypes other than Th1 and Th2 exist and have other patterns of cytokine secretion. The functional significance of Th1 and Th2 cell subsets is that their distinct patterns of cytokine secretion lead to strikingly different T cell actions 4, 5, 6. Th1
Cytokine Studies in Isolated Islets
It is now well documented that cytokines can be cytotoxic to pancreatic islets in vitro7, 8. IL-1, TNFα, TNFβ, and IFNγ (in pico- to nanomolar concentrations) are cytostatic to β-cells: that is, the individual cytokines inhibit insulin synthesis and secretion, but these largely recover after the cytokine is removed. In addition, the cytokines may be cytocidal: i.e. IL-1, TNFα, TNFβ, and IFNγ, usually when added in combination, destroy the β-cells in both rodent and human islets. Because the
TH1 Cells and Cytokines as Mediators of β-Cell Destruction in IDDM
Abundant evidence now suggests that autoreactive T cells are present in the normal immune system but are prevented from expressing their autoreactive potential by other regulatory (suppressor) T cells [47]. The opposing actions of autoreactive and regulatory T cells are regulated by their respective cytokine products 4, 5, 6; one study has provided direct evidence for the operation of such a cytokine immunoregulatory balance in the avoidance of autoimmune diabetes [48]. Diabetes was induced in
Molecular Mechanisms of Cytokine Actions in Islet β-Cells
The actions of IL-1β (as a single agent) on β-cells have been studied the most, but the actions of TNFα and IFNγ (usually in combination with IL-1β) have also been examined, and a variety of mechanisms have been proposed to mediate the cytostatic and/or the cytotoxic effects of these cytokines (IL-1β, TNFα, and IFNγ) on islet β-cells. Most current evidence points to oxygen and/or nitrogen free radicals as mediators of cytokine-induced islet β-cell destruction 7, 8, 65 (Fig. 3).
Therapeutic Perspectives
Present and future approaches to prevention of human IDDM are based on recent findings regarding the roles of cytokines in the autoimmune pathogenesis of β-cell destruction. Thus, current evidence suggests that IDDM results from an immunoregulatory imbalance in which Th1 cells and their cytokine products, IFNγ, IL-2, and TNFβ (Type 1 cytokines), dominate over immunoregulatory (suppressor) Th2 cells and their cytokine products, IL-4 and IL-10 (Type 2 cytokines). Therefore, the current notion is
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