Cytokines and their roles in pancreatic islet β-cell destruction and insulin-dependent diabetes mellitus

Insulin dependent diabetes mellitus (IDDM) is a disease that results from autoimmune destruction of the insulin producing beta-cells in the pancreatic islets of Langerhans. The autoimmune response against islet beta-cells is believed to result from a disorder of immunoregulation. According to this concept, a T helper 1 (Th1) subset of T cells and their cytokine products, i.e. Type 1 cytokines-interleukin 2 (IL 2), interferon gamma (IFN gamma), and tumor necrosis factor beta (TNF beta), dominate over an immunoregulatory (suppressor) Th2 subset of T cells and their cytokine products, i.e. Type 2 cytokines-IL-4 and IL-10. This allows Type 1 cytokines to initiate a cascade of immune/inflammatory processes in the islet (insulitis), culminating in beta-cell destruction. Type 1 cytokines activate (1) cytotoxic T cells that interact specifically with beta-cells and destroy them, and (2) macrophages to produce proinflammatory cytokines (IL-1 and TNF alpha), and oxygen and nitrogen free radicals that are highly toxic to islet beta-cells. Furthermore, the cytokines IL-1, TNF alpha, and IFN gamma are cytotoxic to beta-cells, in large part by inducing the formation of oxygen free radicals, nitric oxide, and peroxynitrite in the beta-cells themselves. Therefore, it would appear that prevention of islet beta-cell destruction and IDDM should be aimed at stimulating the production and/or action of Type 2 cytokines, inhibiting the production and/or action of Type 1 cytokines, and inhibiting the production and/or action of oxygen and nitrogen free radicals in the pancreatic islets. (C) 1998 Elsevier Science Inc.