Human Type 1 Diabetes Mellitus Research Articles

Canine diabetes mellitus demonstrates multiple markers of chronic inflammation including Th40 cell increases and elevated systemic-immune inflammation index, consistent with autoimmune dysregulation.

Canine diabetes mellitus (CDM) is a relatively common endocrine disease in dogs. Many CDM clinical features resemble human type 1 diabetes mellitus (T1DM), but lack of autoimmune biomarkers makes calling the disease autoimmune controversial. Autoimmune biomarkers linking CDM and T1DM would create an alternative model for drug development impacting both human and canine disease. We examined peripheral blood of diagnosed CDM dog patients comparing it to healthy control (HC) dogs. Dogs were recruited to a study at the Colorado State University Veterinary Teaching Hospital and blood samples collected for blood chemistry panels, complete blood counts (CBC), and immunologic analysis. Markers of disease progression such as glycated albumin (fructosamine, the canine equivalent of human HbA1c) and c-peptide were addressed. Significant differences in adaptive immune lymphocytes, innate immune macrophages/monocytes and neutrophils and differences in platelets were detected between CDM and HC based on CBC. Significant differences in serum glucose, cholesterol and the liver function enzyme alkaline phosphatase were also detected. A systemic immune inflammation index (SII) and chronic inflammation index (CII) as measures of dynamic changes in adaptive and innate cells between inflammatory and non-inflammatory conditions were created with highly significant differences between CDM and HC. Th40 cells (CD4+CD40+ T cells) that are demonstrably pathogenic in mouse T1DM and able to differentiate diabetic from non-diabetic subjects in human T1DM were significantly expanded in peripheral blood mononuclear cells. Based on each clinical finding, CDM can be categorized as an autoimmune condition. The association of significantly elevated Th40 cells in CDM when compared to HC or to osteoarthritis, a chronic but non-autoimmune disease, suggests peripheral blood Th40 cell numbers as a biomarker that reflects CDM chronic inflammation. The differences in SII and CII further underscore those findings.

842-P: A Novel Drug to Modulate Autoinflammation and Promote Glucose Control in Type 1 Diabetes Mellitus

NOD mice are the accepted model for Type 1 Diabetes Mellitus (T1DM) Canine Diabetes (CD) demonstrates clinical outcomes identical to NOD and human T1DM. We described helper T cells that express the CD40 receptor, termed Th40 cells. In human T1DM Th40 cells expand significantly in number in peripheral blood prior to hyperglycemia; and respond to human islets. In NOD mice, Th40 cells increase first in the pancreatic lymph nodes, expand in number in the periphery prior to hyperglycemia, are the prominent T cell type detected in the pancreas during insulitis, and transfer diabetes to SCID recipients. Naturally occurring CD is insulin requiring and demonstrates the same clinical parameters as human disease. In a clinical pilot study using diabetic dogs we discovered significantly elevated Th40 cell numbers in PBMC compared to non-diabetic dogs (p < 0.0001) . Th40 cell numbers may help predict risk of development of T1DM as a subset of “at-risk” pre-T1DM human subjects who developed T1DM showed elevated Th40 numbers. Using a novel approach to target CD40-mediated inflammation we created a series of small peptides. The lead candidate, OPT101, has an approved IND and completed Phase 1a human clinical trials establishing human safety profiles. OPT501, a canine version caused a rapid reduction in Th40 cell numbers in diabetic dogs. Daily insulin requirements were reduced on average by 75% and in 2 cases by 90%. Fructosamine, the canine equivalent of HbA1c, was reduced 40.2% on average with 3 subjects achieving normal range. All participants had significantly reduced daily blood glucose averages, and 3 subjects maintained normal glucose levels and time-in-range (TIR) increased to greater than 50%, and in some cases greater than 90%, from a previous TIR of 10%. All participants demonstrated increased c-peptide levels, a measure of restored beta cell function, after 6 weeks of treatment. Equivalent clinical outcomes have not been reported for any other drug candidate in veterinary or human T1DM trials. Disclosure D.H.Wagner: Other Relationship; Op-T, LLC. G.M.Vaitaitis: None. Funding National Institutes of Health (AI131784; AI128592)

A Simplified Streptozotocin-Induced Diabetes Model in Nude Mice.

Preclinical studies of human cellular and tissue-based products (HCT/Ps) for transplantation therapy of type 1 diabetes mellitus (T1DM) necessarily involve animal models, particularly mouse models of diabetes induced by streptozotocin (STZ). These models should mimic the clinical and metabolic manifestations of T1DM in humans (face validity) and be similar to T1DM in terms of the pathogenetic mechanism (construct validity). Furthermore, since HCT/Ps contain human cells, modeling of diabetes in immune-deficient animals is obligatory. Here we describe the most simplified diabetes model in Nude mice. Diabetes was induced in 31 males by a single intraperitoneal injection of STZ in normal saline at a medium-to-high dose of 150 mg/kg body weight. Fourteen control animals received only saline. Non-fasting plasma glucose (PG) levels were measured periodically for 50 days. All STZ-treated mice survived beyond 50 days. By day 15 after STZ administration, 22 of 31 (71%) mice developed stable diabetes based on the following criteria: (1) non-fasting PG ≥ 15 mmol/L on consecutive measurements up until day 50; (2) no diabetes remission. The mean non-fasting PG in mice with stable diabetes over the period of 35 days was equal to 25.7 mmol/L. On day 50, mean plasma insulin concentration, mean pancreatic insulin content, and the average number of β-cells in pancreatic islets were 2.6, 8.4, and 50 times lower, respectively, than in the control animals. We consider that our Nude mouse model of diabetes meets face validity and construct validity criteria and can be used in preclinical studies of HCT/Ps.

Standardization of type 1 and type 2 diabetic nephropathy models in rats: Assessment and characterization of metabolic features and renal injury.

ABSTRACTBackground:Diabetes mellitus and its complications, such as nephropathy, represent a global burden. Recent research focuses on developing drugs that specifically target the pathogenesis of diabetic nephropathy rather than merely treating hyperglycemia. Rodent models of animal disease are integral in drug discovery and represent an obligatory regulatory requirement.Aim:The aim of this study was to develop and standardize rat models of type 1 and type 2 diabetic nephropathy, resembling characteristics of human clinical condition.Materials and Methods:Rats were administered streptozotocin (STZ) 50 mg/kg intraperitoneally (i.p.), and STZ 50 mg/kg i.p. + nicotinamide (NA) 110 mg/kg i.p., for induction of type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM), respectively. Metabolic parameters (body weight, feed and water intake, blood glucose, serum insulin, oral glucose tolerance test, intraperitoneal insulin tolerance test, and indices of insulin sensitivity) were evaluated to characterize the symptoms of T1DM and T2DM. Renal damage was confirmed by the estimation of renal function biomarkers, kidney antioxidant status, kidney hypertrophy index, and histopathology.Results:STZ and STZ + NA administration increased blood glucose levels significantly. Metabolic parameters indicated that administration of STZ resulted in clinical features of human T1DM, whereas STZ + NA rats resembled human T2DM. STZ- and STZ + NA-treated rats developed diabetic nephropathy in 4 weeks, indicated by altered levels of renal function markers, increased kidney hypertrophy index, increased renal oxidative stress, and altered tissue architecture. The study proposes reproducible and cost-effective rat models for both T1DM- and T2DM-induced diabetic nephropathy characterized by stable metabolic features and typical renal lesions.

Results, meta-analysis and a first evaluation of UNOxR, the urinary nitrate-to-nitrite molar ratio, as a measure of nitrite reabsorption in experimental and clinical settings.

We recently found that renal carbonic anhydrase (CA) is involved in the reabsorption of inorganic nitrite (NO2-), an abundant reservoir of nitric oxide (NO) in tissues and cells. Impaired NO synthesis in the endothelium and decreased NO bioavailability in the circulation are considered major contributors to the development and progression of renal and cardiovascular diseases in different conditions including diabetes. Isolated human and bovine erythrocytic CAII and CAIV can convert nitrite to nitrous acid (HONO) and its anhydride N2O3 which, in the presence of thiols (RSH), are further converted to S-nitrosothiols (RSNO) and NO. Thus, CA may be responsible both for the homeostasis of nitrite and for its bioactivation to RSNO/NO. We hypothesized that enhanced excretion of nitrite in the urine may contribute to NO-related dysfunctions in the renal and cardiovascular systems, and proposed the urinary nitrate-to-nitrite molar ratio, i.e., UNOxR, as a measure of renal CA-dependent excretion of nitrite. Based on results from clinical and experimental animal studies, here, we report on a first evaluation of UNOxR. We determined UNOxR values in preterm neonates, healthy children, and adults, in children suffering from type 1 diabetes mellitus (T1DM) or Duchenne muscular dystrophy (DMD), in elderly subjects suffering from chronic rheumatic diseases, type 2 diabetes mellitus (T2DM), coronary artery disease (CAD), or peripheral arterial occlusive disease (PAOD). We also determined UNOxR values in healthy young men who ingested isosorbide dinitrate (ISDN), pentaerythrityl tetranitrate (PETN), or inorganic nitrate. In addition, we tested the utility of UNOxR in two animal models, i.e., the LEW.1AR1-iddm rat, an animal model of human T1DM, and the APOE*3-Leiden.CETP mice, a model of human dyslipidemia. Mean UNOxR values were lower in adult patients with rheumatic diseases (187) and in T2DM patients of the DALI study (74) as compared to healthy elderly adults (660) and healthy young men (1500). The intra- and inter-variabilities of UNOxR were of the order of 50% in young and elderly healthy subjects. UNOxR values were lower in black compared to white boys (314 vs. 483, P = 0.007), which is in line with reported lower NO bioavailability in black ethnicity. Mean UNOxR values were lower in DMD (424) compared to healthy (730) children, but they were higher in T1DM children (1192). ISDN (3 × 30mg) decreased stronger UNOxR compared to PETN (3 × 80mg) after 1day (P = 0.046) and after 5days (P = 0.0016) of oral administration of therapeutically equivalent doses. In healthy young men who ingested NaNO3 (0.1mmol/kg/d), UNOxR was higher than in those who ingested the same dose of NaCl (1709 vs. 369). In LEW.1AR1-iddm rats, mean UNOxR values were lower than in healthy rats (198 vs. 308) and comparable to those in APOE*3-Leiden.CETP mice (151).

Toll-like receptor 3 (TLR3) and the development of type 1 diabetes mellitus.

Type 1 diabetes mellitus (T1DM) is a chronic, progressive autoimmune disease characterized by metabolic decompensation often leading to dehydration and ketoacidosis. Viral agents seem to play an important role in triggering the autoimmune destruction that leads to the development of T1DM. Among several viral strains investigated so far, the enterovirus family has been consistently associated with the onset of T1DM in humans. One of the mediators of viral damage is the double-stranded RNA (dsRNA) generated during replication and transcription of viral RNA and DNA. The Toll-like receptor 3 (TLR3) gene codes for an endoplasmic receptor of the pattern-recognition receptors (PRRs) family that recognizes dsRNA, plays an important role in the innate immune response triggered by viral infection. Binding of dsRNA to the TLR3 triggers the release of proinflammatory cytokines, such as interferons, which exhibit potent antiviral action; thus, protecting uninfected cells and inducing apoptosis of infected ones. Therefore, the TLR3 gene is a good candidate for the development of T1DM. Within this context, the objective of the present review was to address the role of the TLR3 gene in the development of T1DM.

Toll-like receptor 3 is critical for coxsackievirus B4-induced type 1 diabetes in female NOD mice.

Group B coxsackieviruses (CVBs) are involved in triggering some cases of type 1 diabetes mellitus (T1DM). However, the molecular mechanism(s) responsible for this remain elusive. Toll-like receptor 3 (TLR3), a receptor that recognizes viral double-stranded RNA, is hypothesized to play a role in virus-induced T1DM, although this hypothesis is yet to be substantiated. The objective of this study was to directly investigate the role of TLR3 in CVB-triggered T1DM in nonobese diabetic (NOD) mice, a mouse model of human T1DM that is widely used to study both spontaneous autoimmune and viral-induced T1DM. As such, we infected female wild-type (TLR3(+/+)) and TLR3 knockout (TLR3(-/-)) NOD mice with CVB4 and compared the incidence of diabetes in CVB4-infected mice with that of uninfected counterparts. We also evaluated the islets of uninfected and CVB4-infected wild-type and TLR3 knockout NOD mice by immunohistochemistry and insulitis scoring. TLR3 knockout mice were markedly protected from CVB4-induced diabetes compared with CVB4-infected wild-type mice. CVB4-induced T-lymphocyte-mediated insulitis was also significantly less severe in TLR3 knockout mice compared with wild-type mice. No differences in insulitis were observed between uninfected animals, either wild-type or TLR3 knockout mice. These data demonstrate for the first time that TLR3 is 1) critical for CVB4-induced T1DM, and 2) modulates CVB4-induced insulitis in genetically prone NOD mice.

The role of Toll-like receptors and vitamin D in diabetes mellitus type 1--a review.

It is widely accepted that type 1 diabetes mellitus (T1DM) is an autoimmune disease resulting from an interaction between immunologic, genetic and environmental factors. However, the exact mechanism leading to the development of T1DM remains incomplete. There is a large body of evidence pointing towards the important role of toll-like receptor (TLR) activation and vitamin D deficiency in T1DM pathogenesis. In this article, we review the available data on the influence of TLRs' level of activation and vitamin D status on the risk of the development of T1DM in humans and rodent models. We also summarize the current information regarding the interactions between TLRs' level of activation, vitamin D status and various environmental factors, such as enteroviral infections, the gut microbiota and breastfeeding substitution, among others. Our results stipulate that vitamin D seems to protect against T1DM by reducing the TLRs' level of activation.

The role of interferon induced with helicase C domain 1 (IFIH1) in the development of type 1 diabetes mellitus

Type 1 diabetes mellitus (T1DM) is a chronic, progressive, autoimmune disease characterized by metabolic decompensation frequently leading to dehydration and ketoacidosis. Viral pathogens seem to play a major role in triggering the autoimmune destruction that leads to the development of T1DM. Among several viral strains investigated so far, enteroviruses have been consistently associated with T1DM in humans. One of the mediators of viral damage is the double-stranded RNA (dsRNA) generated during replication and transcription of viral RNA and DNA. The IFIH1 gene encodes a cytoplasmic receptor of the pattern-recognition receptors (PRRs) family that recognizes dsRNA, playing a role in the innate immune response triggered by viral infection. Binding of dsRNA to this PRR triggers the release of proinflammatory cytokines, such as interferons (IFNs), which exhibit potent antiviral activity, protecting uninfected cells and inducing apoptosis of infected cells. The IFIH1 gene appears to play a major role in the development of some autoimmune diseases, and it is, therefore, a candidate gene for T1DM. Within this context, the objective of the present review was to address the role of IFIH1 in the development of T1DM.

A Variable CD3+ T-Cell Frequency in Peripheral Blood Lymphocytes Associated with Type 1 Diabetes Mellitus Development in the LEW.1AR1-iddm Rat

PurposeThe LEW.1AR1-iddm rat is an animal model of human type 1 diabetes mellitus (T1DM), which arose through a spontaneous mutation within the MHC-congenic inbred strain LEW.1AR1 (RT1r2). In contrast to the diabetes-resistant LEW.1AR1 background strain in LEW.1AR1-iddm rats a highly variable T-cell frequency could be observed in peripheral blood lymphocytes (PBLs).MethodsIn this study we therefore characterised the T-cell repertoire within the PBLs of the two strains by flow cytometry analysis and identified the CD3+ T-cell phenotype and its possible linkage to diabetes susceptibility. To map loci conferring susceptibility to variable CD3+ T-cell frequency, backcross strains (N2) were generated with the genetically divergent BN and PAR rats for microsatellite analysis.ResultsThe LEW.1AR1-iddm rat strain was characterised by a higher variability of CD3+ T-cells in PBLs along with a slightly decreased mean value compared to the LEW.1AR1 background strain. The reason for this reduction was a decrease in the CD4+ T-cell count while the CD8+ T-cell proportion remained unchanged. However, both T-cell subpopulations showed a high variability. This resulted in a lower CD4+/CD8+ T-cell ratio than in LEW.1AR1 rats. Like LEW.1AR1-iddm rats all animals of the backcross populations, N2 BN and N2 PAR rats, also showed large variations of the CD3+ T-cell frequency. The phenotype of variable CD3+ T-cell frequency mapped to the telomeric region of chromosome 1 (RNO1), which is identical with the already known Iddm8 diabetes susceptibility region. The data indicate that a variable CD3+ T-cell frequency in PBLs is genetically linked to diabetes susceptibility in the LEW.1AR1-iddm rat.ConclusionThe T-cell variability in PBLs could be related to the previously reported imbalance between regulatory and effector T-cell populations which results in beta-cell autoimmunity. Since similar T-cell phenotypes have also been described in human T1DM the identification of the functional role of the observed variable CD3+ T-cell frequency may help to understand the mechanisms of autoimmunity in T1DM.

Toll-like receptor 3 involvement in Coxsackievirus B 4 acceleration of type 1 diabetes. (P6134)

Abstract Viruses are important in the pathogenesis of type 1 diabetes mellitus (T1DM). A pancreatrophic strain of coxsackievirus, CVB4, which is associated with the development of T1DM in humans, accelerates the development of T1DM in NOD mice. Toll-Like Receptor 3 (TLR3) is activated by viral dsRNA and is broadly expressed by NOD mice and human pancreatic beta cells, suggesting that TLR3 signaling may be important in CVB4 acceleration of T1DM. We used NOD mice deficient in TLR3 (TLR3 KO) to test the hypothesis that TLR3 signaling is important in CVB4 acceleration of T1DM in NOD mice. We report that TLR3 KO NOD mice are markedly protected from CVB4 acceleration of T1DM compared to wild type (WT) NOD mice. Similarly, we have observed that phenylmethimazole (C10), which has recently been shown to inhibit dsRNA-triggered TLR3 signaling, also delays CVB4 acceleration of T1DM in NOD mice. In preliminary experiments to investigate the mechanism by which TLR3 deficiency provides protection from T1DM in this model, we observed marked differences in T regulatory cell populations between TLR3 KO and WT NOD mice, and a significant enhancement of viral clearance in C10-treated NOD mice. These results indicate the distinct importance of TLR3 signaling in environmental (i.e. viral) induction of T1DM and that C10 could potentially protect β cells from virus-induced insulitis.

Prevention and treatment of type 1 diabetes mellitus by the manipulation of invariant natural killer T cells

Invariant natural killer T (iNKT) cells are CD1d-restricted T cells with regulatory functions. iNKT cells are numerically and functionally deficient in experimental models of type 1 diabetes mellitus (T1DM). Moreover, various experimental strategies correcting the defect of or stimulating iNKT cells prevent T1DM. Here, we review the data on the role of iNKT cells in the development of T1DM and discuss indications, obstacles and prospects of the use of iNKT cell manipulations in the prevention and treatment of human T1DM.

Insulin Is a Stronger Inducer of Insulin Resistance than Hyperglycemia in Mice with Type 1 Diabetes Mellitus (T1DM)

Subjects with type 1 diabetes mellitus (T1DM) eventually develop insulin resistance and other features of T2DM such as cardiovascular disorders. The exact mechanism has been not been completely understood. In this study, we tested the hypothesis that excessive or inappropriate exposure to insulin is a primary mediator of insulin resistance in T1DM. We found that continuous exposure of mice with non-obese diabetes to insulin detemir, which is similar to some current conventional treatment of human T1DM, induced severe insulin resistance, whereas untreated hyperglycemia for the same amount of time (2 weeks) did not cause obvious insulin resistance. Insulin resistance was accompanied by decreased mitochondrial production as evaluated by mitochondrial DNA and levels of transcripts and proteins of mitochondrion-associated genes, increased ectopic fat accumulation in liver and skeletal muscle (gastrocnemius) evaluated by measurements of triglyceride content, and elevated oxidative stress detected by the GSH/GSSG ratio. Prolonged exposure of cultured hepatocytes to insulin induced significant insulin resistance, whereas the same length of exposure to a high level of glucose (33 mm) did not cause obvious insulin resistance. Furthermore, our results showed that prolonged exposure to insulin caused oxidative stress, and blockade of mitochondrion-derived oxidative stress by overexpression of manganese-superoxide dismutase prevented insulin resistance induced by the prolonged exposure to insulin. Together, our results show that excessive exposure to insulin is a primary inducer of insulin resistance in T1DM in mice.

Commonality in the genetic control of Type 1 diabetes in humans and NOD mice: variants of genes in the IL-2 pathway are associated with autoimmune diabetes in both species

Variants within the IL-2 (interleukin 2) and CD25 genes are associated with T1DM (Type 1 diabetes mellitus) in mice and humans respectively. Both gene products are essential for optimal immune tolerance and a partial failure to tolerize is linked to the autoimmune responses to insulin and other beta-cell proteins that precede T1DM onset. Gene variants that contribute to common disease susceptibility often alter gene expression only modestly. Small expression changes can be technically challenging to measure robustly, especially since biological variation usually contributes negatively to this goal. The present review focuses on allele-specific expression assays that can be used to quantify genotype-determined expression differences such as those observed for IL-2, where the susceptibility allele is transcribed 2-fold less than the resistance allele.

Abnormal NF-κB Function Characterizes Human Type 1 Diabetes Dendritic Cells and Monocytes

Dendritic cell (DC) differentiation is abnormal in type 1 diabetes mellitus (T1DM). However, the nature of the relationship between this abnormality and disease pathogenesis is unknown. We studied the LPS response in monocytes and monocyte-derived DCs isolated from T1DM patients and from non-T1DM controls. In T1DM patients, late LPS-mediated nuclear DNA binding by RelA, p50, c-Rel, and RelB was impaired as compared with type 2 DM, rheumatoid arthritis, and healthy subjects, associated with impaired DC CD40 and MHC class I induction but normal cytokine production. In TIDM monocytes, RelA and RelB were constitutively activated, and the src homology 2 domain-containing protein tyrosine phosphatase (SHP-1), a negative regulator of NF-kappaB, was overexpressed. Addition of sodium stibogluconate, a SHP-1 inhibitor, to DCs differentiating from monocyte precursors restored their capacity to respond to LPS in approximately 60% of patients. The monocyte and DC NF-kappaB response to LPS is thus a novel phenotypic and likely pathogenetic marker for human T1DM. SHP-1 is at least one NF-kappaB regulatory mechanism which might be induced as a result of abnormal inflammatory signaling responses in T1DM monocytes.

A Mini Meta‐Analysis of Studies on CD4+CD25+ T cells in Human Type 1 Diabetes

Type 1 diabetes mellitus (T1DM) is characterized by a loss of self-tolerance to islet antigens. In health, immunological tolerance is maintained by multiple central and peripheral mechanisms including the action of a specialized set of regulatory T cells characterized by expression of CD4 and CD25 (CD4+CD25+ Treg). It has been suggested that a defect in this cell population, either numerically or functionally, could contribute to the development of autoimmune diseases, such as T1DM. To investigate this possibility, several research groups have studied the frequency and suppressive capacity of this cell population in individuals with T1DM and, to date, there are four such studies published. We therefore performed a mini meta-analysis to compare the results in the four published studies, account for differences in their findings, and draw a consensus view on the role of this important cell subset in human T1DM.

Combined treatment with lisofylline and exendin-4 reverses autoimmune diabetes

Type 1 diabetes mellitus (T1DM) is an autoimmune disease leading to near complete pancreatic β-cell destruction. New evidence suggests that β-cell regeneration is possible, but ongoing autoimmune damage prevents restoration of β-cell mass. We tested the hypothesis that simultaneously blocking autoimmune cytokine damage and supplying a growth-promoting stimulus for β-cells would provide a novel approach to reverse T1DM. Therefore, in this study we combined lisofylline to suppress autoimmunity and exendin-4 to enhance β-cell proliferation for treating autoimmune-mediated diabetes in the non-obese diabetic (NOD) mouse model. We found that this combined therapy effectively reversed new-onset diabetes within a week of therapy, and even maintained euglycemia up to 145 days after treatment withdrawal. The therapeutic effect of this regimen was associated with improved β-cell metabolism and insulin secretion, while reducing β-cell apoptosis. It is possible that such combined therapy could become a new strategy to defeat T1DM in humans.

NKT Cells and IFN-γ Establish the Regulatory Environment for the Control of Diabetogenic T Cells in the Nonobese Diabetic Mouse

In type 1 diabetes mellitus (T1DM), T cell-mediated destruction of insulin-producing pancreatic beta cells leads to the acute onset of hyperglycemia. The nonobese diabetic mouse model of human T1DM reveals that T cells capable of inducing diabetes can escape normal central tolerance, and can cause T1DM if left unchecked. However, several regulatory T cell subsets can temper autoaggressive T cells, although it remains undetermined when and how, and by which subset, homeostatic control of diabetogenic T cells is normally achieved in vivo. Using a cotransfer model, we find that NKT cells efficiently dampen the action of diabetogenic CD4+ T cells, and do so in an indirect manner by modifying the host environment. Moreover, the NKT cell-containing population modifies the host via production of IFN-gamma that is necessary for driving the inhibition of diabetogenic T cells in vivo.

B cells in autoimmune diabetes.

Autoantibodies have been used as good markers for the prediction of future development of type 1 diabetes mellitus (T1DM), but are not thought to be pathogenic in this disease. The role of B cells that produce autoantibodies in the pathogenesis of human T1DM is largely unknown. In the non-obese diabetic (NOD) mouse model of autoimmune diabetes, it has been shown that B cells may contribute multifariously to the pathogenesis of the disease. Some aspects of deficiencies of B cell tolerance may lead to the circulation of autoreactive B cells. In addition, the antigen-presenting function of autoantigen specific B cells is likely to be particularly important, and autoantibodies are also considered to play a critical role. This review discusses the possible aspects of B cells involved in the development of autoimmune diabetes.