Animal Models Of Insulin-dependent Diabetes Mellitus Research Articles

IL-17A is involved in diabetic inflammatory pathogenesis by its receptor IL-17RA.

The participation of interleukin (IL)-17A in diabetic pathogenesis is suggested in animal models of autoimmune diabetes and in patients with type 1 diabetes (T1D), but with some contradictory results. Particularly, evidence for a direct injury of IL-17A to pancreatic β cells is lacking. We showed that IL-17A deficiency alleviated diabetic signs including hyperglycemia, hypoinsulinemia, and inflammatory response in Ins2Akita (Akita) mice, a T1D model with spontaneous mutation in insulin 2 gene leading to β-cell apoptosis. IL-17A enhanced inflammatory reaction, oxidative stress, and cell apoptosis but attenuated insulin level in mouse insulin-producing MIN6 cells. IL-17A had also a synergistic destruction to MIN6 cells with streptozotocin (STZ), a pancreatic β-cell-specific cytotoxin. Blocking IL-17 receptor A (IL-17RA) reduced all these deleterious effects of IL-17A on MIN6 cells. The results demonstrate the role and the importance of IL-17A in T1D pathogenesis and suggest a potential therapeutic strategy for T1D targeting IL-17A and/or IL-17RA.

Sphingolipids in Type 1 Diabetes: Focus on Beta-Cells.

Type 1 diabetes (T1DM) is a chronic autoimmune disease, with a strong genetic background, leading to a gradual loss of pancreatic beta-cells, which secrete insulin and control glucose homeostasis. Patients with T1DM require life-long substitution with insulin and are at high risk for development of severe secondary complications. The incidence of T1DM has been continuously growing in the last decades, indicating an important contribution of environmental factors. Accumulating data indicates that sphingolipids may be crucially involved in T1DM development. The serum lipidome of T1DM patients is characterized by significantly altered sphingolipid composition compared to nondiabetic, healthy probands. Recently, several polymorphisms in the genes encoding the enzymatic machinery for sphingolipid production have been identified in T1DM individuals. Evidence gained from studies in rodent islets and beta-cells exposed to cytokines indicates dysregulation of the sphingolipid biosynthetic pathway and impaired function of several sphingolipids. Moreover, a number of glycosphingolipids have been suggested to act as beta-cell autoantigens. Studies in animal models of autoimmune diabetes, such as the Non Obese Diabetic (NOD) mouse and the LEW.1AR1-iddm (IDDM) rat, indicate a crucial role of sphingolipids in immune cell trafficking, islet infiltration and diabetes development. In this review, the up-to-date status on the findings about sphingolipids in T1DM will be provided, the under-investigated research areas will be identified and perspectives for future studies will be given.

Prospects for primary prevention of type 1 diabetes by restoring a disappearing microbe

Prevention of childhood-onset type 1 diabetes has become more urgent with its marked increased incidence in recent decades in the modern world. Temporally associated with the rising incidence of type 1 diabetes, as well as other autoimmune and allergic diseases in childhood in modern times, is the disappearance of Bifidobacterium and specifically Bifidobacterium longum subsp. infantis (B. infantis) predominance in the intestinal microbiota of breastfed, vaginally-delivered infants. B. infantis efficiently metabolizes human milk oligosaccharides (HMOs) without cross-feeding free sugar monomers to other commensals or pathogens and thereby dominates the intestinal microbiota of breastfed infants. Increased levels of short-chain fatty acids (SCFA), which stimulate both immunoregulation and healthy intestinal and pancreatic β-cell function, are generated by B. infantis. Based on recent observations of the intestinal microbiota in early life in young children who develop type 1 diabetes and demonstration of the robust preventive effects of SCFA in animal models of autoimmune diabetes, we hypothesize that restoring a B. infantis-dominant microbiota early in infancy will prevent islet autoimmunity and childhood-onset type 1 diabetes.

Peripherally induced regulatory T cells contribute to the control of autoimmune diabetes in the NOD mouse model

Type 1 diabetes (T1D) results from the autoimmune destruction of pancreatic beta cells and is partly caused by deficiencies in the Foxp3+ regulatory T-cell (Treg) compartment. Conversely, therapies that increase Treg function can prevent autoimmune diabetes in animal models. The majority of Tregs develop in the thymus (tTregs), but a proportion of Foxp3+ Tregs is generated in the periphery (pTregs) from Foxp3- CD4+ T-cell precursors. Whether pTregs play a distinct role in T1D has not yet been explored. We report here that pTregs are a key modifier of disease in the nonobese diabetic (NOD) mouse model for T1D. We generated NOD mice deficient for the Foxp3 enhancer CNS1 involved in pTreg induction. We show that CNS1 knockout decreased the frequency of pTregs and increased the risk of diabetes. Our results show that pTregs fulfill an important non-redundant function in the prevention of beta cell autoimmunity that causes T1D.

11-Keto-β-Boswellic Acid Inhibits Lymphocyte (CD3) Infiltration Into Pancreatic Islets of Young None Obese Diabetic (NOD) Mice

11-Keto-β-Boswellic acid (KBA) has been shown to prevent infiltration of lymphocytes into pancreatic islets and appearance of peri-insular apoptotic cells in an animal model of autoimmune diabetes caused by injection of Multiple Low Doses of Streptozotocin (MLD-STZ), which is a chemical compound belonging to the class of nitrososureas. The aim of this work was to study whether or not KBA can also prevent/attenuate infiltration of lymphocytes into pancreatic islets and appearance of peri-insular apoptotic cells in an animal model of autoimmune diabetes caused by genetic dysfunction resembling human type 1 diabetes in several important features. Four weeks old female NOD mice received daily i.p. injections of 7.5 mg/kg of KBA over a period of 3 weeks. Compared to 4 weeks old animals there was significant infiltration of lymphocytes (CD3) into pancreatic islets and appearance of peri-insular apoptotic cells in the period between 4 and 7 weeks. During this time plasma glucose dropped significantly and body weight did not increase. As far as pro-inflammatory cytokines are concerned, except a small increase of IFN-γ, there was no change in the blood. In mice that had been treated with KBA between 4 and 7 weeks after birth no significant infiltration of lymphocytes into pancreatic islets and appearance of peri-insular apoptotic cells was observed, when compared to 4 weeks old mice. Moreover, there was no drop of blood glucose and the animals gained body weight. It is concluded that - similar to the model of MLD-STZ-diabetes - also in the NOD mouse model KBA is able to attenuate or even prevent development of insulitis, suggesting that KBA protects islets from autoimmune reaction regardless whether the signal is provided by a chemical compound or by genetic dysfunction. Whether this also holds for human type 1 diabetes remains to be established.

Islet-Derived CD4 T Cells Targeting Proinsulin in Human Autoimmune Diabetes.

Type 1 diabetes results from chronic autoimmune destruction of insulin-producing β-cells within pancreatic islets. Although insulin is a critical self-antigen in animal models of autoimmune diabetes, due to extremely limited access to pancreas samples, little is known about human antigenic targets for islet-infiltrating T cells. Here we show that proinsulin peptides are targeted by islet-infiltrating T cells from patients with type 1 diabetes. We identified hundreds of T cells from inflamed pancreatic islets of three young organ donors with type 1 diabetes with a short disease duration with high-risk HLA genes using a direct T-cell receptor (TCR) sequencing approach without long-term cell culture. Among 85 selected CD4 TCRs tested for reactivity to preproinsulin peptides presented by diabetes-susceptible HLA-DQ and HLA-DR molecules, one T cell recognized C-peptide amino acids 19-35, and two clones from separate donors responded to insulin B-chain amino acids 9-23 (B:9-23), which are known to be a critical self-antigen-driving disease progress in animal models of autoimmune diabetes. These B:9-23-specific T cells from islets responded to whole proinsulin and islets, whereas previously identified B:9-23 responsive clones from peripheral blood did not, highlighting the importance of proinsulin-specific T cells in the islet microenvironment.

Human Type 1 Diabetes Is Characterized by an Early, Marked, Sustained, and Islet-Selective Loss of Sympathetic Nerves.

In humans, the glucagon response to moderate-to-marked insulin-induced hypoglycemia (IIH) is largely mediated by the autonomic nervous system. Because this glucagon response is impaired early in type 1 diabetes, we sought to determine if these patients, like animal models of autoimmune diabetes, have an early and severe loss of islet sympathetic nerves. We also tested whether this nerve loss is a permanent feature of type 1 diabetes, is islet-selective, and is not seen in type 2 diabetes. To do so, we quantified pancreatic islet and exocrine sympathetic nerve fiber area from autopsy samples of patients with type 1 or 2 diabetes and control subjects without diabetes. Our central finding is that patients with either very recent onset (<2 weeks) or long duration (>10 years) of type 1 diabetes have a severe loss of islet sympathetic nerves (Δ = −88% and Δ = −79%, respectively). In contrast, patients with type 2 diabetes lose no islet sympathetic nerves. There is no loss of exocrine sympathetic nerves in either type 1 or type 2 diabetes. We conclude that patients with type 1, but not type 2, diabetes have an early, marked, sustained, and islet-selective loss of sympathetic nerves, one that may impair their glucagon response to IIH.

Fecal Microbiota Composition Differs Between Children With β-Cell Autoimmunity and Those Without

The role of the intestinal microbiota as a regulator of autoimmune diabetes in animal models is well-established, but data on human type 1 diabetes are tentative and based on studies including only a few study subjects. To exclude secondary effects of diabetes and HLA risk genotype on gut microbiota, we compared the intestinal microbiota composition in children with at least two diabetes-associated autoantibodies (n = 18) with autoantibody-negative children matched for age, sex, early feeding history, and HLA risk genotype using pyrosequencing. Principal component analysis indicated that a low abundance of lactate-producing and butyrate-producing species was associated with β-cell autoimmunity. In addition, a dearth of the two most dominant Bifidobacterium species, Bifidobacterium adolescentis and Bifidobacterium pseudocatenulatum, and an increased abundance of the Bacteroides genus were observed in the children with β-cell autoimmunity. We did not find increased fecal calprotectin or IgA as marker of inflammation in children with β-cell autoimmunity. Functional studies related to the observed alterations in the gut microbiome are warranted because the low abundance of bifidobacteria and butyrate-producing species could adversely affect the intestinal epithelial barrier function and inflammation, whereas the apparent importance of the Bacteroides genus in development of type 1 diabetes is insufficiently understood.

FTY720 preserved islet β‐cell mass by inhibiting apoptosis and increasing survival of β‐cells in db/db mice

FTY720, an analogue of sphingosine-1-phosphate, has shown potential in the treatment of several autoimmune diseases, such as multiple sclerosis, type 1 diabetes and systemic lupus erythematosus. It prevents development or cure of autoimmune diabetes in animal models. Recently, we reported that FTY720 also prevents development of diabetes in db/db mice by β-cell regeneration in vivo. This study investigated the effect of FTY720 on apoptosis in β-cells in db/db mice treated with FTY720 16 weeks. Six week old female db/db mice were divided into control and FTY720 groups. FTY720 (10 mg/kg) was orally administrated daily. Body weights and fasting glucose levels were measured once a week after overnight fasting. After 16 weeks of treatment, oral glucose and insulin tolerance tests were performed, serum insulin levels and insulin contents in pancreas were determined, and then all mice were subjected to physiological and histological analyses. FTY720-treated mice showed normal fasting glucose levels, improved glucose tolerance with normal insulin sensitivity and restored β-cell function to produce and secret insulin. Pancreas histology revealed that FTY720 prevented islet damage and preserved β-cell mass by inhibiting apoptosis and increasing β-cell survival in pancreatic islets. We concluded that early intervention with FTY720 in db/db mice can prevent development of diabetes through preserving β-cell mass by inhibiting apoptosis and increasing survival of islet β-cells.

Reduced numbers of dendritic cells with a tolerogenic phenotype in the prediabetic pancreas of NOD mice

The NOD mouse is a widely used animal model of autoimmune diabetes. Prior to the onset of lymphocytic insulitis, DCs accumulate at the islet edges. Our recent work indicated that these DCs may derive from aberrantly proliferating local precursor cells. As CD8α(+) DCs play a role in tolerance induction in steady-state conditions, we hypothesized that the autoimmune phenotype might associate with deficiencies in CD8α(+) DCs in the prediabetic NOD mouse pancreas. We studied CD8α(+) DCs in the pancreas and pLNs of NOD and control mice, focusing on molecules associated with tolerance induction (CD103, Langerin, CLEC9A, CCR5). mRNA expression levels of tolerance-modulating cytokines were studied in pancreatic CD8α(+) DCs of NOD and control mice. In the NOD pancreas, the frequency of CD8α(+)CD103(+)Langerin(+) cells was reduced significantly compared with control mice. NOD pancreatic CD8α(+)CD103(+)Langerin(+) DCs expressed reduced levels of CCR5, CLEC9A, and IL-10 as compared with control DCs. These alterations in the CD8α(+)CD103(+)Langerin(+) DC population were not present in pLNs. We demonstrate local abnormalities in the CD8α(+) DC population in the prediabetic NOD pancreas. These data suggest that abnormal differentiation of pancreatic DCs contributes to loss of tolerance, hallmarking the development of autoimmune diabetes.

On the Immense Variety and Complexity of Circumstances Conditioning Pancreatic β-Cell Apoptosis in Type 1 Diabetes

In his masterpiece War and Peace (1869), Leo Tolstoy wrote: “The human intellect with no inkling of the immense variety and complexity of circumstances conditioning a phenomenon, any one of which may be separately conceived as the cause of it, snatches at the first and the most easily understood approximation, and says: ‘Oh, here is the cause!’” The field of type 1 diabetes has been plagued by this trend for oversimplification. As a result, individual pathways are often suggested as “the cause” of this complex, multifactorial, and probably heterogeneous disease, thereby leading to therapeutic attempts that nearly always end in failure. MicroRNAs (miRNAs) are a family of endogenous single-stranded RNA molecules around 22 nucleotides in length (1). They are highly conserved among species and regulate the expression of partially complementary protein-coding genes by either degrading or preventing translation of target messenger RNAs. miRNAs are transcribed from individual genes, located in exons or introns of protein-coding genes or in intergenic regions, and are often clustered (2). Importantly, >50% of human genes may be at least in part regulated by miRNAs (3), adding an extra level of regulation for gene expression. An article by Roggli et al. (4) published in this issue of Diabetes describes a microarray analysis on islets obtained from 4- and 8-week-old female NOD mice (an animal model of autoimmune diabetes, in which 4-week-old animals have little or no immune infiltration whereas 8-week-old mice show insulitis in most islets; hyperglycemia usually starts after 14 weeks of age). They observed a preferential increase in miR-29a/b/c in the islets obtained from 8-week-old animals, a finding confirmed by other methods in …

Is the origin of type 1 diabetes in the gut?

In type 1 diabetes, insulin-producing beta-cells in the pancreas are destroyed by immune-mediated mechanisms. The manifestation of the disease is preceded by the so-called pre-diabetic period that may last several years and is characterized by the appearance of circulating autoantibodies against beta-cell antigens. The role of the gut as a regulator of type 1 diabetes was suggested in animal studies, in which changes affecting the gut immune system modulated the incidence of diabetes. Dietary interventions, alterations in the intestinal microbiota and exposure to enteric pathogens, regulate the development of autoimmune diabetes in animal models. It has been demonstrated that these modulations affect the gut barrier mechanisms and intestinal immunity. Because the pancreas and the gut belong to the same intestinal immune system, the link between autoimmune diabetes and the gut is not unexpected. The gut hypothesis in the development of type 1 diabetes is also supported by the observations made in human type 1 diabetes. Early diet could modulate the development of beta-cell autoimmunity; weaning to hydrolysed casein formula decreased the risk of beta-cell autoimmunity by age 10 in the infants at genetic risk. Increased gut permeability, intestinal inflammation with impaired regulatory mechanisms and dysregulated oral tolerance have been observed in children with type 1 diabetes. The factors that contribute to these intestinal alterations are not known, but interest is focused on the microbial stimuli and function of innate immunity. It is likely that our microbial environment does not support the healthy maturation of the gut and tolerance in the gut, and this leads to the increasing type 1 diabetes as well as other immune-mediated diseases regulated by intestinal immune system. Thus, the interventions, aiming to prevent or treat type 1 diabetes in humans, should be targeting the gut immune system.

Gut Microbiota and Type 1 Diabetes

The gut immune system has a key role in the development of autoimmune diabetes, and factors that control the gut immune system are also regulators of beta-cell autoimmunity. Gut microbiota modulate the function of the gut immune system by their effect on the innate immune system, such as the intestinal epithelial cells and dendritic cells, and on the adaptive immune system, in particular intestinal T cells. Due to the immunological link between gut and pancreas, e.g. the shared lymphocyte homing receptors, the immunological changes in the gut are reflected in the pancreas. According to animal studies, changes in gut microbiota alter the development of autoimmune diabetes. This has been demonstrated by antibiotics that induce changes in the gut microbiota. Furthermore, gut-colonizing microbes may modify the incidence of autoimmune diabetes in animal models. Deficient toll-like receptor (TLR) signaling, mediating microbial stimulus in immune cells, prevents autoimmune diabetes, which appears to be dependent on alterations in the intestinal microbiota. Although few studies have been conducted in humans, recent studies suggest that the abundance of Bacteroides and lack of butyrate-producing bacteria in fecal microbiota are associated with beta-cell autoimmunity and type 1 diabetes. It is possible that altered gut microbiota are associated with immunological aberrancies in type 1 diabetes. The changes in gut microbiota could lead to alterations in the gut immune system, such as increased gut permeability, small intestinal inflammation, and impaired tolerance to food antigens, all of which are observed in type 1 diabetes. Poor fitness of gut microbiota could explain why children who develop type 1 diabetes are prone to enterovirus infections, and do not develop tolerance to cow milk antigens. These candidate risk factors of type 1 diabetes may imply an increased risk of type 1 diabetes due to the presence of gut microbiota that do not support health. Despite the complex interaction of microbiota, host, environment, and disease mechanisms, gut microbiota are promising novel targets in the prevention of type 1 diabetes.

The gut as a regulator of early inflammation in type 1 diabetes

Several studies indicate that factors affecting the gut are capable of modulating the development of autoimmune diabetes. This review discusses the recent research on these mechanisms, which may reveal novel pathogenic pathways and new possibilities for prevention of type 1 diabetes (T1D). The role of the gut as a regulator of T1D is mainly based on animal studies in which changes affecting the gut immune system have been shown to modulate the immune-mediated destruction of insulin-producing beta-cells. Dietary interventions, alterations in the intestinal microbiota and exposure to enteral pathogens regulate the development of autoimmune diabetes in animal models. In several studies, it has been demonstrated that these modulations affect the gut barrier mechanisms and intestinal immunity. Also, in humans, increased gut permeability and intestinal inflammation are associated with T1D. A recent report of dietary intervention study in infants at genetic risk of T1D showed that early diet could modulate the development of beta-cell autoimmunity in humans; weaning to hydrolyzed casein formula decreased the risk of beta-cell autoimmunity by age 10. The gut modulation affecting permeability, inflammation and microbiota is evidently associated with the regulation of the inflammation leading to beta-cell destruction. Although the mechanisms of action are not fully understood, the recent research points out the lines of approach for the prevention of T1D.

Induction of diabetes with signs of autoimmunity in primates by the injection of multiple-low-dose streptozotocin

AimTo develop a preclinical large animal model of autoimmune diabetes to facilitate the translational research of autoimmune diabetes in human. Materials and methodsNine young rhesus monkeys received multiple-low-dose (MLD) intravenous injections of streptozotocin for five consecutive days, followed by two additional boosting injections of STZ given 1week apart. The induction of autoimmune diabetes was evaluated by regular metabolic testing, serological assessment of islet-reactive autoantibodies and histological examination of pancreatic tissues. ResultsSeven of nine treated animals became diabetic with moderate hyperglycemia initially and more severe hyperglycemia thereafter. All diabetic animals exhibited severely impaired glucose tolerance, limited islet function, and required insulin therapy to maintain relatively normal glucose metabolism and healthy status. Serological tests showed that all diabetic monkeys developed autoantibodies specifically against insulin and islet antigens. Furthermore, histological examination of the pancreata from diabetic animals revealed evidence of specific destruction of islet β cells and islets infiltrated with T lymphocytes. Overt and persistent diabetes can be induced in young rhesus monkeys by the injection of MLD-STZ, and autoimmune responses to pancreatic islet cells seem to be involved in the development of glucose intolerance and diabetes. ConclusionThese data indicate for the first time that autoimmune diabetes can be induced in primates; this may serve as a valuable preclinical model for studying the pathogenesis of and potential therapies for autoimmune diabetes in humans.

B cell depletion in autoimmune diabetes: insights from murine models

Introduction: The incidence of type 1 diabetes (T1D) is rising for reasons that largely elude us. New strategies aimed at halting the disease process are needed. One type of immune cell thought to contribute to T1D is the B lymphocyte. The first Phase II trial of B cell depletion in new onset T1D patients indicated that this slowed the destruction of insulin-producing pancreatic beta cells. The mechanistic basis of the beneficial effects remains unclear.Areas covered: Studies of B cell depletion and deficiency in animal models of T1D. How B cells can influence T cell-dependent autoimmune diabetes in animal models. The heterogeneity of B cell populations and current evidence for the potential contribution of specific B cell subsets to diabetes, with emphasis on marginal zone B cells and B1 B cells.Expert opinion: B cells can influence the T cell response to islet antigens and B cell depletion or genetic deficiency is associated with decreased insulitis in animal models. New evidence suggests that B1 cells may contribute to diabetes pathogenesis. A better understanding of the roles of individual B cell subsets in disease will permit fine-tuning of therapeutic strategies to modify these populations.

Immunomodulation with microbial vaccines to prevent type 1 diabetes mellitus

Selected bacteria, viruses, parasites and nonliving, immunologically active microbial substances prevent autoimmune diabetes in animal models. Such agents might also have a protective effect in humans by providing immune stimuli critical during childhood development. The 'hygiene hypothesis' proposes that reduced exposure to environmental stimuli, including microbes, underlies the rising incidence of childhood autoimmune diseases, including type 1 diabetes mellitus (T1DM). This hypothesis is supported by data that highlight the importance of infant exposure to environmental microbes for appropriate development of the immune system, which might explain the observation that administration of microbes or their components inhibits autoimmune disease in animals. This finding raises the possibility of using live, nonpathogenic microbes (for example, probiotics) or microbial components to modulate or 're-educate' the immune system and thereby vaccinate against T1DM. Progress has been assisted by the identification of receptors and pathways through which gut microbes influence development of the immune system. Such mechanistic data have moved a field that was once regarded as being on the scientific fringe to the mainstream, and support increased funding to advance this promising area of research in the hope that it might deliver the long awaited answer of how to safely prevent T1DM.

Mucosal Insulin Vaccination for Type 1 Diabetes Prevention

Mucosal administration of autoantigen, if efficacious, is an attractive therapeutic approach for prevention of type 1 diabetes. It can prevent or delay autoimmune diabetes in animal models, but although shown to be safe has not yet been proven effective in human studies. Efficacy may depend upon the dose and route at which antigen is administered, the stage in type 1 diabetes pathogenesis at which treatment is initiated, and the study cohort that is treated. Here we address these issues and propose a clinical translation possibility for mucosal insulin administration in genetically at risk individuals.

Modulating the natural history of type 1 diabetes in children at high genetic risk by mucosal insulin immunization

Mucosal administration of insulin represents an attractive antigen-specific therapeutic approach to preventing type 1 diabetes. It can prevent autoimmune diabetes in animal models, but although it has been shown to be safe, it has not yet been proven effective in human studies. Efficacy may depend on the dose and route at which insulin is administered, the stage in type 1 diabetes pathogenesis at which treatment is initiated, and the study cohort that is treated. We have proposed Pre-POINT (Primary Oral/intranasal INsulin Trial), a dose-finding safety and immune efficacy pilot study for primary mucosal insulin therapy in islet autoantibody-negative children at high genetic risk for type 1 diabetes who naturally first develop autoimmunity to insulin. Pre-POINT aims to identify an optimal insulin dose and route of application (orally or intranasally) that is well tolerated and can induce an immune response to insulin for additional use in a phase II/III primary prevention trial in children at risk.

Interferon-tau inhibits the development of diabetes in NOD mice

Interferon-alpha (IFN-α) inhibits the development of diabetes in animal models of autoimmune diabetes. However, the mechanism of the action is not fully understood and drug toxicity could limit its potential clinical utility. Interferon-tau (IFN-τ) is another type 1 interferon, which has less toxicity but may have different biologic activity than IFN-α. This study explores the effect of IFN-τ on the diabetic process in non-obese diabetic (NOD) mice. IFN-τ by intraperitoneal, subcutaneous, or oral routes of administration decreased the development of spontaneous diabetes in NOD mice. Islet inflammation was decreased 50%. IFN-τ administration to recipient mice prevented the development of passively transferred and cyclophosphamide accelerated diabetes. IFN-τ treatment also decreased anti-islet effector activity of NOD splenic cells. Immunoregulatory activity of splenic cells was augmented by IFN-τ administration as was the number of splenic CD25+CD4+ cells. Concanavalin A (Con A)-induced release of IFN-γ was decreased in spleen cells from IFN-τ treated mice. In conclusion, IFN-τ inhibits spontaneous autoimmune diabetes and passively transferred diabetes in the NOD mouse. This diabetes sparing activity may be due to an induction of regulatory cells, possibly CD25+CD4+ T cells, which in turn inhibit anti-islet effector cell activity and the development of insulitis and diabetes. Due to the lower drug toxicity, IFN-τ could be a better drug candidate than IFN-α for experimental clinical trials.