Correlation studies between cytokines expressed in islets and autoimmune diabetes development in NOD mice and BB rats have demonstrated that -cell destructive insulitis is associated with increased expression of proinflammatory cytokines (IL-1, TNF␣, and IFN␣) and type 1 cytokines (IFN␥, TNF, IL-2 and IL-12), whereas non-destructive (benign) insulitis is associated with increased expression of type 2 cytokines (IL-4 and IL-10) and the type 3 cytokine (TGF). Cytokines (IL-1, TNF␣, TNF and IFN␥) may be directly cytotoxic to -cells by inducing nitric oxide and oxygen free radicals in the -cells. In addition, cytokines may sensitize -cells to T-cell-mediated cytotoxicity in vivo by upregulating MHC class I expression on the -cells (an action of IFN␥), and inducing Fas (CD95) expression on -cells (actions of IL-1, and possibly TNF␣ and IFN␥). Transgenic expression of cytokines in -cells of non-diabetes-prone mice and NOD mice has suggested pathogenic roles for IFN␣, IFN␥, IL-2 and IL-10 in insulin-dependent diabetes mellitus (IDDM) development, and protective roles for IL-4, IL-6 and TNF␣. Systemic administrations of a wide variety of cytokines can prevent IDDM development in NOD mice and/or BB rats; however, a given cytokine may retard or accelerate IDDM development, depending on the dose and frequency of administration, and the age and the diabetes-prone animal model studied (NOD mouse or BB rat). Islet-reactive CD4 + T-cell lines and clones that adoptively transfer IDDM into young NOD mice have a Th1 phenotype (IFN␥-producing), but other islet-specific Th1 clones that produce TGF can adoptively transfer protection against IDDM in NOD mice. NOD mice with targeted deletions of IL-12 and IFN␥ genes still develop IDDM, albeit delayed and slightly less often. In contrast, post-natal deletions of IL-12 and IFN␥, also IL-1, TNF␣, IL-2, and IL-6-by systemic administrations of neutralizing antibodies, soluble receptors and receptor antagonists, and receptor-targeted cytotoxic drugs-significantly decrease IDDM incidence in NOD mice and/or BB rats. These cytokine deletion studies have provided the best evidence for pathologic roles for proinflammatory cytokines (IL-1, TNF␣, and IL-6) and type 1 cytokines (IFN␥, IL-2 and IL-12) in IDDM development.