Experimental Animals

1986

DOI: 10.1538/expanim1978.35.4_495

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Absence of Insulitis and Overt Diabetes in Athymic Nude Mice with NOD Genetic Background

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Yoshio Kishimoto

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Cited by 59 publications

(34 citation statements)

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“…For some time, questions have been raised concerning the action of TNF in chronic autoimmune states (30)(31)(32), such as systemic lupus erythematosus [modeled by the NZW/NZB F1 hybrid mouse (33)(34)(35)] and type 1 diabetes [modeled by mice of the nonobese diabetic (NOD) strain (36)]. Whereas passive immunization of such animals might not be practical given the long latent period of the disease, the use of the TNF inhibitor expression system described here will allow an assessment of the importance of this and other cytokines in the pathogenesis of autoimmunity.…”

Section: Discussionmentioning

confidence: 99%

Prolonged and effective blockade of tumor necrosis factor activity through adenovirus-mediated gene transfer.

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et al. 1994

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

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A chimeric protein capable of binding and neutralizing tumor necrosis factor (TNF) and lymphotoxin was expressed in mice transduced with a replication-incompetent adenoviral vector into which a TNF inhibitor gene had been engineered. Within 3 days following the injection of 109 infectious particles, the TNF inhibitor concentration exceeded 1 mg/ml of plasma; this level of expression was maintained for at least 4 weeks, and detectable TNF inhibitory activity was measured 6 weeks after injection of the recombinant virus.

“…For some time, questions have been raised concerning the action of TNF in chronic autoimmune states (30)(31)(32), such as systemic lupus erythematosus [modeled by the NZW/NZB F1 hybrid mouse (33)(34)(35)] and type 1 diabetes [modeled by mice of the nonobese diabetic (NOD) strain (36)]. Whereas passive immunization of such animals might not be practical given the long latent period of the disease, the use of the TNF inhibitor expression system described here will allow an assessment of the importance of this and other cytokines in the pathogenesis of autoimmunity.…”

Section: Discussionmentioning

confidence: 99%

Prolonged and effective blockade of tumor necrosis factor activity through adenovirus-mediated gene transfer.

¹

,

²

,

³

et al. 1994

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

View full text Add to dashboard Cite

A chimeric protein capable of binding and neutralizing tumor necrosis factor (TNF) and lymphotoxin was expressed in mice transduced with a replication-incompetent adenoviral vector into which a TNF inhibitor gene had been engineered. Within 3 days following the injection of 109 infectious particles, the TNF inhibitor concentration exceeded 1 mg/ml of plasma; this level of expression was maintained for at least 4 weeks, and detectable TNF inhibitory activity was measured 6 weeks after injection of the recombinant virus.

“…In these mice overt diabetes develops spontaneously in a majority of female mice and less frequently in male mice. As in human insulin-dependent diabetes mellitus, development of overt diabetes in NOD mice is preceded by infiltration of lymphoid cells into the pancreatic islets and is observed only after massive destruction of insulin-producing f3 cells (2).…”

mentioning

confidence: 98%

The phenotype of lymphoid cells and thymic epithelium correlates with development of autoimmune insulitis in NOD in equilibrium with C57BL/6 allophenic chimeras.

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et al. 1991

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

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The mechanisms contributing to the development of autoimmune insulin-dependent diabetes mellitus have been analyzed in allophenic mouse chimeras of the NOD +* C57BL/6 strain combination (where NOD is nonobese diabetic). Occurrence of lymphoid cell infiltration (insulitis) in pancreatic islets was observed in the majority of such chimeras. The development of insulitis was found to correlate with major histocompatibility complex chimerism in lymphoid cells and in thymus cortical regions. Chimeras with more than 50% of C57BL/6 lymphoid cells rarely developed insulitis. Our data suggest that the correlation with the thymic cortical region is absolute. Thus, all individuals displaying NOD or NOD/ C57BL/6 thymic cortical regions developed insulitis, whereas we have not observed insulitis in chimeras with only C57BL/6 thymic cortical regions. Thus the positive selection of T cells appears to play a crucial role in the development of insulindependent diabetes mellitus.One of the best animal models of human insulin-dependent diabetes mellitus is represented by the nonobese diabetic (NOD) mouse (1). In these mice overt diabetes develops spontaneously in a majority of female mice and less frequently in male mice. As in human insulin-dependent diabetes mellitus, development of overt diabetes in NOD mice is preceded by infiltration of lymphoid cells into the pancreatic islets and is observed only after massive destruction of insulin-producing f3 cells (2).Predisposition to the disease is under polygenic control, one of the genes having been identified as the major histocompatibility complex (MHC) class II locus both in man and in the NOD mouse strain (3, 4). The involvement of MHC genes in the development of autoimmunity in NOD mice indicates that T cells play a crucial role in this process. Indeed, the disease can be transferred with cells from diabetic animals (5) requiring both CD4+ and CD8+ cells (6, 7). NOD mice express a unique I-A molecule (I-ANOi) where aspartic acid in position 57 ofthe 13 chain is replaced by serine (8). This is observed also in the HLA-DQ ,8 chain of many Caucasians with insulin-dependent diabetes mellitus (9-11). The I-E antigen is absent in the NOD strain due to a defect in I-E a chain expression (3). Recent reports showing that insulitis in NOD mice can be prevented by the introduction of I-E a chain or non-NOD I-A transgenes have supported the hypothesis that I-A and I-E expression affects development of insulitis (12-15).I-E expression is known to mediate intrathymic clonal deletion of sets of T-cell antigen receptors carrying specific 13-chain variable regions (16, 17). Based on these observations, the protective effect of I-E has been suggested to reflect negative selection through intrathymic clonal deletion of potentially hazardous T-cell clones (12, 18). However, the observation that NOD mice expressing promoter-mutated I-E a chain genes mediating intrathymic deletion of I-Ereactive T cells still develop insulitis has cast doubt about this hypothesis (19).To further investigate t...

“…NOD mice exhibit massive infiltrates of lymphoid cells and macrophages into pancreatic islets (insulitis) prior to complete betacell destruction, and insulitis appears as early as 5 weeks of age. Makino and co-workers [4] have shown that T cells play an important role in the development of insulitis and diabetes in nude NOD mice. The major infiltrating cell populations in the insulitis lesion are CD4 § (L3T4, helper) and CD8 § (Ly2, cytotoxic/suppressor) T cells, and macrophages [5].…”

Section: Discussionmentioning

confidence: 99%

Reactive oxygen intermediates in autoimmune islet cell destruction of the NOD mouse induced by peritoneal exudate cells (rich in macrophages) but not T cells

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et al. 1994

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SummaryThe non-obese diabetic (NOD) mouse spontaneously develops autoimmune Type i (insulindependent) diabetes mellitus. NOD mice exhibit massive infiltrates of T cells and macrophages into pancreatic islets (insulitis) prior to diabetes. The contribution of oxygen free radicals to the development of insulitis in NOD mice was examined by administration of its scavengers, such as superoxide dismutase and catalase. Bovine superoxide dismutase and catalase were each coupled to polyethylene glycol. The treatment with superoxide dismutase-polyethylene glycol reduced the number of islets with insulitis and increased the undamaged islet tissue, as compared with the control group. The treatment with catalase-polyethylene glycol showed a similar tendency which did not reach significance. Using a flow cytometric assay of the oxidation of 2', 7'-dichlorofluorescein, the content of reactive oxygen intermediates in islet cells in the culture system was measured and the effect of peritoneal exudate cells and T cells on their production examined. Peritoneal exudate cells, but not T cells, from NOD mice increased the content of reactive oxygen intermediates in islet cells of either the NOD mouse or the ILI mouse (MHC-identical to NOD); the addition of snperoxide dismutase to the culture medium suppressed this increase in NOD or ILI islet cells. The present data support the concept that production of oxygen free radicals mediated by macrophages can damage islet beta cells, directly resulting in autoimmune Type i diabetes in NOD mice. [Diabetologia (1994) 37: 22-31] Key words NOD mice, insulitis, reactive oxygen intermediates, superoxide dismutase, peritoneal macrophages.Lymphoid cell infiltration into pancreatic islets (insulitis) is a well-recognized feature of Type i (insulindependent) diabetes mellitus both in humans [1] and in rodents with spontaneous diabetes [2,3]. The nonobese diabetic (NOD) mouse spontaneously develops an insulin-dependent diabetes. NOD mice exhibit massive infiltrates of lymphoid cells and macrophages into pancreatic islets (insulitis) prior to complete betacell destruction, and insulitis appears as early as 5 weeks of age. Makino and co-workers [4] have shown

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