Dynamic interaction between T cell-mediated β-cell damage and β-cell repair in the run up to autoimmune diabetes of the NOD mouse

Vukkadapu, Sankaranand S.; Belli, Jenine; Ishii, Koji; Jegga, Anil G.; Hutton, John J.; Aronow, Bruce J.; Katz, Jonathan D.

doi:10.1152/physiolgenomics.00173.2004

Cited by 75 publications

(71 citation statements)

References 71 publications

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“…This result demonstrates TNF has significant effects on both CD4 + and CD8 + T cells. In NOD islets, TNF gene expression has been reported to peak at or before the onset of diabetes (48)(49)(50). We hypothesize that increased TNF expression in mice deleteriously effects regulatory T cell number and function and the deficiency in TNFR1 on regulatory T cells prevents this effect.…”

Section: Discussionmentioning

confidence: 90%

TNF Receptor 1 Deficiency Increases Regulatory T Cell Function in Nonobese Diabetic Mice

Chee

Angstetra

Mariana

et al. 2011

The Journal of Immunology

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TNF has been implicated in the pathogenesis of type 1 diabetes. When administered early in life, TNF accelerates and increases diabetes in NOD mice. However, when administered late, TNF decreases diabetes incidence and delays onset. TNFR1-deficient NOD mice were fully protected from diabetes and only showed mild peri-insulitis. To further dissect how TNFR1 deficiency affects type 1 diabetes, these mice were crossed to β cell-specific, highly diabetogenic TCR transgenic I-Ag7–restricted NOD4.1 mice and Kd-restricted NOD8.3 mice. TNFR1-deficient NOD4.1 and NOD8.3 mice were protected from diabetes and had significantly less insulitis compared with wild type NOD4.1 and NOD8.3 controls. Diabetic NOD4.1 mice rejected TNFR1-deficient islet grafts as efficiently as control islets, confirming that TNFR1 signaling is not directly required for β cell destruction. Flow cytometric analysis showed a significant increase in the number of CD4+CD25+Foxp3+ T regulatory cells in TNFR1-deficient mice. TNFR1-deficient T regulatory cells were functionally better at suppressing effector cells than were wild type T regulatory cells both in vitro and in vivo. This study suggests that blocking TNF signaling may be beneficial in increasing the function of T regulatory cells and suppression of type 1 diabetes.

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Section: Discussionmentioning

confidence: 90%

TNF Receptor 1 Deficiency Increases Regulatory T Cell Function in Nonobese Diabetic Mice

Chee

Angstetra

Mariana

et al. 2011

The Journal of Immunology

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“…On the other hand, other studies have emphasized the role of IL-17 in diabetes development in NOD mice. For example, it was shown that IL-17 transcripts increased during the evolution of diabetes in NOD mice (11) and that Th17 lymphocytes are activated in type 1 diabetic mice (15). Interestingly, in multiple low dose streptozotocin-induced diabetic mice, another murine model of type 1 diabetes, streptozotocin-stimulated IL-17 secretion promoted nitric oxidedependent toxic inflammatory responses toward MIN6, a mouse insulinoma cell line (10).…”

Section: Discussionmentioning

confidence: 99%

“…Komiyama et al (8) reported that IL-17 deficiency did not affect hyperglycemia in NOD mice, whereas other studies have emphasized the role of IL-17 in diabetes development (9 -14). For example, IL-17 mRNA was increased during the development of diabetes in NOD mice (11), and Th17 lymphocytes were activated in type 1 diabetic mice (15). Interestingly, the use of glutamic acid decarboxylase-derived peptide 206 -220-specific approaches to treat type 1 diabetes in NOD mice revealed that adjuvant-free antigens induced IFN␥ and controlled blood glucose via concomitant suppression of IL-17 secretion (9).…”

mentioning

confidence: 99%

Berberine Differentially Modulates the Activities of ERK, p38 MAPK, and JNK to Suppress Th17 and Th1 T Cell Differentiation in Type 1 Diabetic Mice

Cui

Qin

Zhang

et al. 2009

Journal of Biological Chemistry

178

125

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Berberine, an alkaloid derivative from Berberis vulgaris L., has been used extensively in traditional Chinese medicine to treat diarrhea and diabetes, but the underlying mechanisms for treating diabetes are not fully understood. Recent studies suggested that berberine has many beneficial biological effects, including anti-inflammation. Because type 1 diabetes is caused by T cellmediated destruction of ␤ cells and severe islet inflammation, we hypothesized that berberine could ameliorate type 1 diabetes through its immune regulation properties. Here we reported that 2 weeks of oral administration of berberine prevented the progression of type 1 diabetes in half of the NOD mice and decreased Th17 and Th1 cytokine secretion. Berberine suppressed Th17 and Th1 differentiation by reducing the expression of lineage markers. We found that berberine inhibited Th17 differentiation by activating ERK1/2 and inhibited Th1 differentiation by inhibiting p38 MAPK and JNK activation. Berberine down-regulated the activity of STAT1 and STAT4 through the suppression of p38 MAPK and JNK activation, and it controlled the stability of STAT4 through the ubiquitin-proteasome pathway. Our findings indicate that berberine targets MAPK to suppress Th17 and Th1 differentiation in type 1 diabetic NOD mice. This study revealed a novel role of ERK in Th17 differentiation through down-regulation of STAT3 phosphorylation and ROR␥t expression.

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“…Although the role of IL-17-producing cells in the development of diabetes has not been definitively addressed, it has been suggested that these cells may contribute to the pathogenicity of autoreactive T cells in the disease (19,20). The recently elucidated role for IL-21 in the development of Th17 cells (6-8) therefore suggested that Th17 cells might play a role in the IL-21-mediated development of diabetes, and increased IL-17 levels have been identified in the later phase of progression from insulitis to active diabetes (21). We investigated the development of Th17 cells in the prediabetic stage in NOD/WT and NOD/Il21r-KO mice.…”

Section: Normal T Cell Populations and Cytokine Production In Nod/il2mentioning

confidence: 99%

IL-21 signaling is critical for the development of type I diabetes in the NOD mouse

Spolski

Kashyap

Robinson

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

188

161

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IL-21 is a pleiotropic type I cytokine that shares the common cytokine receptor ␥ chain and plays important roles for normal Ig production, terminal B cell differentiation to plasma cells, and Th17 differentiation. IL-21 is elevated in several autoimmune diseases, and blocking its action has attenuated disease in MRL/lpr mice and in collagen-induced arthritis. The diabetes-associated Idd3 locus is at the Il2/Il21 locus, and elevated IL-21 was observed in the nonobese diabetic (NOD) mouse and suggested to contribute to diabetes by augmenting T cell homeostatic proliferation. To determine the role of IL-21 in diabetes, Il21r-knockout (KO) mice were backcrossed to NOD mice. These mice were devoid of lymphocytic infiltration into the pancreas, and only 1 of 20 animals had an elevated glucose compared with 60% of NOD mice on a wild-type (WT) background. Although TCR and Treg-related responses were normal, these mice had reduced Th17 cells and significantly higher levels of mRNAs encoding members of the Reg (regenerating) gene family whose transgenic expression protects against diabetes. Our studies establish a critical role for IL-21 in the development of type I diabetes in the NOD mouse, with obvious potential implications for type I diabetes in humans. Reg genes ͉ Th17 cellsH uman type I diabetes is an autoimmune disease that results from the autoreactive destruction of pancreatic ␤ cells and subsequent loss of insulin production (1). Nonobese diabetic (NOD) mice develop a similar disease and serve as a model system for studying the mechanisms involved in the initiation and propagation of the autoimmune response (2). Although it has been established that ␤ islet cell destruction is initiated by proinflammatory CD4 ϩ and CD8 ϩ T cells infiltrating the pancreas, the molecular mechanisms and cytokine pathways that control this process are not fully understood.IL-21 is a type I cytokine (3) that is the most recently discovered member of the family of cytokines that share the common cytokine receptor ␥ chain, ␥ c (4) . ␥ c is also shared by IL-2, IL-4, IL-7, IL-9, and IL-15 and is mutated in humans with X-linked severe combined immunodeficiency (XSCID) (5). IL-21 is produced most abundantly by CD4 ϩ T cells, including Th17 lineage cells (6-8) and natural killer T (NKT) cells (9), and is known to act on both lymphoid and nonlymphoid target cells, thus controlling both innate and adaptive immune responses (4). IL-21 is critical for normal Ig production (10), can cooperatively drive expansion of CD8 ϩ T cells (11), can activate NK cells (12), and drives terminal B cell differentiation into plasma cells (13). IL-21 has been implicated as playing a role in the development of B cell-mediated lupus-like autoimmune disease based on studies in the BXSB-Yaa (13), Sanroque (14), and MRL/lpr mice (15), and treatment with a soluble IL-21R-Fc fusion protein was shown to lead to a partial decrease in disease severity in the MRL/lpr mice (15) and collagen-induced arthritis (16). In experimental allergic encephalitis (EAE), a model for ...

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Dynamic interaction between T cell-mediated β-cell damage and β-cell repair in the run up to autoimmune diabetes of the NOD mouse

Abstract: . Dynamic interaction between T cell-mediated ␤-cell damage and ␤-cell repair in the run up to autoimmune diabetes of the NOD mouse.

Cited by 75 publications

References 71 publications

TNF Receptor 1 Deficiency Increases Regulatory T Cell Function in Nonobese Diabetic Mice

TNF Receptor 1 Deficiency Increases Regulatory T Cell Function in Nonobese Diabetic Mice

Berberine Differentially Modulates the Activities of ERK, p38 MAPK, and JNK to Suppress Th17 and Th1 T Cell Differentiation in Type 1 Diabetic Mice

IL-21 signaling is critical for the development of type I diabetes in the NOD mouse

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