Transfer of Autoimmune Diabetes Mellitus with Splenocytes from Nonobese Diabetic (NOD) Mice

Wicker, Linda S.; Miller, Barry W.; Mullen, Yoko

doi:10.2337/diab.35.8.855

Cited by 277 publications

(149 citation statements)

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“…Thus, a clear autoaggressive potential of CD4 + T cells was seen, in line with several studies on BB-DP rats and NOD mice [7][8][9][10][11][12]. The predominant role of CD4 + T cells has been previously demonstrated by selective transfer of CD4 + or CD8 + T cells in immunodeficient NOD strains, whereas CD8 + T cell subsets were not diabetogenic [7,16].…”

Section: Discussionsupporting

confidence: 85%

“…The only difference between the LEW.1AR1-iddm rat and the background strain is a mutation on chromosome 1 within Iddm8 (RNO1q43-51) [4,5]. Adoptive transfer of T cells from diabetic LEW.1AR1-iddm rats to prediabetic LEW.1AR1-iddm rats significantly increased the incidence of diabetes [6] in agreement with studies on NOD mice and BB-DP rats [7][8][9][10][11][12]. The autoreactive potential can be transferred through immune cells from diabetic LEW.1AR1-iddm rats into athymic nude LEW.1AR1-Whn rnu animals, but not to the diabetes-resistant LEW.1AR1 background strain [6].…”

Section: Introductionsupporting

confidence: 80%

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Prevention of spontaneous immune-mediated diabetes development in the LEW.1AR1-iddm rat by selective CD8+ T cell transfer is associated with a cytokine shift in the pancreas-draining lymph nodes

et al. 2009

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Aims/hypothesis The LEW.1AR1-iddm rat is an animal model of spontaneous type 1 diabetes mellitus. This study analysed how adoptive transfer of selective T cell subpopulations affects the incidence of diabetes. Methods CD4 + or CD8 + T cells were isolated from diabetic LEW.1AR1-iddm rats or diabetes-resistant LEW.1AR1 rats. Cells were selectively transferred into athymic LEW.1AR1-Whn rnu or prediabetic LEW.1AR1-iddm rats. The animals were monitored for blood glucose, islet infiltration and immune cell composition of pancreas-draining lymph nodes. Results After adoptive transfer of CD4 + T cells from diabetic LEW.1AR1-iddm rats into athymic LEW.1AR1-Whn rnu rats, 50% of the recipients developed diabetes. Transfer of CD8 + T cells failed to induce diabetes. Only 10% of the athymic recipients became diabetic after cotransfer of CD4 + and CD8 + T cells. Adoptive transfer of CD8 + T cells from LEW.1AR1 or diabetic LEW.1AR1-iddm rats into prediabetic LEW.1AR1-iddm rats significantly reduced the incidence of diabetes. In protected normoglycaemic animals regulatory CD8 + /CD25 + and CD4 + /CD25 + T cell subpopulations that were also FOXP3-positive accumulated in the pancreas-draining lymph nodes. In this lymphatic organ, gene expression of anti-inflammatory cytokines was significantly higher than in diabetic rats. Conclusions/interpretation Our results show that adoptive transfer of CD4 + but not CD8 + T cells from diabetic LEW.1AR1-iddm rats induced diabetes development. Importantly, CD8 + T cells from diabetic LEW.1AR1-iddm rats and diabetes-resistant LEW.1AR1 rats provided protection against beta cell destruction. The accumulation of regulatory T cells in the pancreas-draining lymph nodes from protected rats indicates that transferred CD8 + T cells may have beneficial effects in the control of beta cell autoimmunity. Keywords

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Section: Discussionsupporting

confidence: 85%

Section: Introductionsupporting

confidence: 80%

Prevention of spontaneous immune-mediated diabetes development in the LEW.1AR1-iddm rat by selective CD8+ T cell transfer is associated with a cytokine shift in the pancreas-draining lymph nodes

et al. 2009

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“…NOD mice spontaneously develop autoimmune diabetes with immunopathological features resembling those of human disease and can be used as an animal model to study the pathogenesis of T1D. Previous studies have demonstrated that transfer of NOD CD4 1 T cells to immunodeficient NOD/SCID mice can induce diabetes in those recipients, indicating that CD4 1 T cells play an important role in the pathogenesis of diabetes [3,4]. Th1 cells have been closely linked with diabetic pathogenesis because IFN-g and IL-12 are upregulated in the inflammatory lesions in the pancreas and administration of IL-12 promotes autoimmune diabetes in NOD mice [5][6][7].…”

Section: Introductionmentioning

confidence: 99%

Attenuation of Th1 response through galectin‐9 and T‐cell Ig mucin 3 interaction inhibits autoimmune diabetes in NOD mice

2009

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Galectin-9 (gal-9), widely expressed in many tissues, regulates Th1 cells and induces their apoptosis through its receptor, T-cell Ig mucin 3, which is mainly expressed on terminally differentiated Th1 cells. Type 1 diabetes is a Th1-dominant autoimmune disease that specifically destroys insulin-producing b cells. To suppress the Th1 immune response in the development of autoimmune diabetes, we overexpressed gal-9 in NOD mice by injection of a plasmid encoding gal-9. Mice treated with gal-9 plasmid were significantly protected from diabetes and showed less severe insulitis compared with controls. Flow cytometric analyses in NOD-T1/2 double transgenic mice showed that Th1-cell population in spleen, pancreatic lymph node and pancreas was markedly decreased in gal-9 plasmidtreated mice, indicating a negative regulatory role of gal-9 in the development of pathogenic Th1 cells. Splenocytes from gal-9 plasmid-treated mice were less responsive to mitogenic stimulation than splenocytes from the control group. However, adoptive transfer of splenocytes from gal-9-treated or control mice caused diabetes in NOD/SCID recipients with similar kinetics, suggesting that gal-9 treatment does not induce active tolerance in NOD mice. We conclude that gal-9 may downregulate Th1 immune response in NOD mice and could be used as a therapeutic target in autoimmune diabetes.Key words: Galectin-9 . Th1 . T-cell Ig mucin 3 . Type 1 diabetes IntroductionWhen CD4 1 Th cells interact with class II MHC-peptide complex and costimulatory molecules on APC, they differentiate into several effector subsets. There are two major Th subsets that have unique patterns of cytokine secretion and different functional properties. Th1 cells produce cytokines such as IFN-g, IL-2, TNF-a and lymphotoxin that are commonly associated with cellmediated immune responses against intracellular pathogens, delayed-type hypersensitivity and induction of organ-specific autoimmune diseases. Th2 cells produce cytokines such as IL-4, IL-5, IL-10 and IL-13 that are crucial for controlling extracellular helminth infections and promoting atopic and allergic diseases [1,2].Type 1 diabetes (T1D) is a T-cell-mediated autoimmune disease that selectively destroys the insulin-producing b cells in the pancreas. NOD mice spontaneously develop autoimmune diabetes with immunopathological features resembling those of human disease and can be used as an animal model to study the pathogenesis of T1D. Previous studies have demonstrated that transfer of NOD CD4 1 T cells to immunodeficient NOD/SCID mice can induce diabetes in those recipients, indicating that CD4 1 T cells play an important role in the pathogenesis of diabetes [3,4] [12]. Previous approaches using TIM-3-Ig fusion protein to interrupt the interactions between TIM-3 and its ligand in vivo resulted in hyperproliferation of Th1 cells and release of Th1-related cytokines [13]. TIM-3 ligand was subsequently identified as galectin-9 (gal-9) [14], a b-galactoside binding lectin that belongs to a growing family of animal lectins, the...

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“…First, the CY-accelerated diabetes model was chosen to test whether peptide immunization could counteract the effect of CY, which is secondary to abrogation of suppressor T cell function [15,16]. Second, to investigate whether active cellular mechanisms were associated with suppression of diabetes, splenocytes from peptide-immunized animals were cotransferred together with diabetes into young NOD mice using splenocytes from diabetic NOD donors [17]. Finally, T cell proliferation to the immunizing peptide or a panel of other synthetic peptides was investigated.…”

Section: Introductionmentioning

confidence: 99%

Immunization of non-obese diabetic (NOD) mice with glutamic acid decarboxylase-derived peptide 524–543 reduces cyclophosphamide-accelerated diabetes

Saı̈¹,

Rivereau²,

Granier

et al. 1996

Clinical and Experimental Immunology

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SUMMARYNOD mice constitute a model for studying the prevention of human autoimmune type 1 diabetes. Glutamic acid decarboxylase (GAD) could be a key antigen involved in this disease, and GAD65 peptide 524-543 has been implicated in early T cell response in young NOD mice. We performed two i.p. injections of GAD peptide 524-543 (100 ¹ g at each injection), together with Freund's incomplete adjuvant (FIA), into female NOD mice at 30 and 45 days old. Diabetes was accelerated 2 weeks later by a single injection of cyclophosphamide (CY), which acts against suppressive mechanisms. Treatment with GAD 524-543 peptide delayed the onset of diabetes and reduced its incidence (28% versus 60%; P < 0 . 001) compared with control mice injected with FIA alone, or GAD peptide 534-553, or an irrelevant peptide. In the same group, the severity of lymphocytic inflammation of pancreatic islets was reduced (P < 0 . 03). Up to 3 months after peptide injections, a strong splenocytic proliferative response occurred in immunized NOD mice against the immunizing peptide alone (but not against a panel of seven other GAD65-derived peptides). After peptide challenge of splenocytes in vitro, protection against CY-accelerated diabetes was associated with higher peptide-specific production of T helper type 2 (Th2)-associated interleukins 4 and 10, whereas Th1-associated interferon-gamma and IL-2 were proportionally less represented. During cotransfer, T splenocytes from GAD 524-543-immunized mice were able to reduce the capacity of T cells from diabetic donors to transfer the disease adoptively (P < 0 . 01), demonstrating the generation of cellular mechanisms that actively suppress the disease. It is concluded that immunization of NOD mice with GAD65 peptide 524-543 can counteract CYaccelerated diabetes, possibly through active cellular suppression linked to a shift of Th1/Th2 balance toward the production of Th2 cytokines such as IL-4 and IL-10. This study provides additional support for the notion that GAD, and more precisely its epitope 524-543, could be one of the key targets for the pathogenesis of type 1 diabetes in NOD mice, as well as for the efficacy of disease-specific peptide therapy in type 1 diabetes.

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Transfer of Autoimmune Diabetes Mellitus with Splenocytes from Nonobese Diabetic (NOD) Mice

Cited by 277 publications

References 0 publications

Prevention of spontaneous immune-mediated diabetes development in the LEW.1AR1-iddm rat by selective CD8+ T cell transfer is associated with a cytokine shift in the pancreas-draining lymph nodes

Prevention of spontaneous immune-mediated diabetes development in the LEW.1AR1-iddm rat by selective CD8+ T cell transfer is associated with a cytokine shift in the pancreas-draining lymph nodes

Attenuation of Th1 response through galectin‐9 and T‐cell Ig mucin 3 interaction inhibits autoimmune diabetes in NOD mice

Immunization of non-obese diabetic (NOD) mice with glutamic acid decarboxylase-derived peptide 524–543 reduces cyclophosphamide-accelerated diabetes

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