Roles of cytokines in the pathogenesis and therapy of type 1 diabetes.
Type 1 diabetes (T1D) results from autoimmune destruction of the insulin-producing beta-cells in the pancreatic islets of Langerhans by autoreactive T helper 1 (Th1) cells characterized by their cytokine secretory products, interleukin-2 (IL-2) and interferon gamma (IFNgamma). Th1-type cytokines (IL-2 and IFNgamma) correlate with T1D, whereas Th2 (IL-4 and IL-10), Th3 (transforming growth factor beta [TGFbeta]), and T regulatory cell-type cytokines (IL-10 and TGFbeta) correlate with protection from T1D. Paradoxically, however, administrations of Th1-type cytokines (IL-2 and IFNgamma) and immunotherapies that induce Th1-type cytokine responses actually prevent T1D, at least in animal models. Therefore, immunotherapies that inhibit IL-2 production/action will block Th1 cell/cytokine-driven effector mechanisms of pancreatic islet beta-cell destruction; however, anti-IL-2 therapy will not allow immune tolerance to be established. In contrast, immunotherapies that increase IL-2 production/action may correct an immunodeficiency in IL-2 production that appears to underlie the autoimmunity of T1D, thereby restoring immune tolerance to islet beta-cells and prevention of T1D.
Rabinovitch
Alex
A
Department of Medicine, University of Alberta, Edmonton, AB, Canada. alex.rabinovitch@ualberta.ca
Suarez-Pinzon
Wilma L
WL
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D016207:Cytokines / Q000378:metabolism* / Q000494:pharmacology / Q000627:therapeutic use; D003922:Diabetes Mellitus, Type 1 / Q000188:drug therapy / Q000209:etiology / Q000378:metabolism*; D006801:Humans; D007108:Immune Tolerance / Q000187:drug effects; D050417:Insulin-Secreting Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D007376:Interleukin-2 / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D016688:Mice, Inbred NOD; D018448:Models, Immunological; D020123:Sirolimus / Q000494:pharmacology / Q000627:therapeutic use; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D018417:Th1 Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D018418:Th2 Cells / Q000276:immunology / Q000378:metabolism
D016207:Cytokines; D007376:Interleukin-2; D020123:Sirolimus