Genetic Absence of γ-Interferon Delays but Does Not Prevent Diabetes in NOD Mice

Hultgren, Bruce; Huang, Xiaojian; Dybdal, Noël; Stewart, Timothy A.

doi:10.2337/diab.45.6.812

Cited by 184 publications

(89 citation statements)

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“…According to our model, blockade of IFN-␥ is also expected to inhibit ␤ cell death and diabetes, although IFN-␥ itself does not exert apoptosis on islet cells. Ablation of the IFN-␥ gene in NOD mice did not completely prevent diabetes; however, the development of diabetes was delayed (49). Anti-IFN-␥ Ab (50) or targeted disruption of IFN-␥R (51) abrogated diabetes in NOD mice.…”

Section: Discussionmentioning

confidence: 99%

IFN-γ/TNF-α Synergism as the Final Effector in Autoimmune Diabetes: A Key Role for STAT1/IFN Regulatory Factor-1 Pathway in Pancreatic β Cell Death

Suk

Kim

et al. 2001

The Journal of Immunology

208

187

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Fas ligand (FasL), perforin, TNF-α, IL-1, and NO have been considered as effector molecule(s) leading to β cell death in autoimmune diabetes. However, the real culprit(s) in β cell destruction have long been elusive, despite intense investigation. We and others have demonstrated that FasL is not a major effector molecule in autoimmune diabetes, and previous inability to transfer diabetes to Fas-deficient nonobese diabetic (NOD)-lpr mice was due to constitutive FasL expression on lymphocytes from these mice. Here, we identified IFN-γ/TNF-α synergism as the final effector molecules in autoimmune diabetes of NOD mice. A combination of IFN-γ and TNF-α, but neither cytokine alone, induced classical caspase-dependent apoptosis in insulinoma and pancreatic islet cells. IFN-γ treatment conferred susceptibility to TNF-α-induced apoptosis on otherwise resistant insulinoma cells by STAT1 activation followed by IFN regulatory factor (IRF)-1 induction. IRF-1 played a central role in IFN-γ/TNF-α-induced cytotoxicity because inhibition of IRF-1 induction by antisense oligonucleotides blocked IFN-γ/TNF-α-induced cytotoxicity, and transfection of IRF-1 rendered insulinoma cells susceptible to TNF-α-induced cytotoxicity. STAT1 and IRF-1 were expressed in pancreatic islets of diabetic NOD mice and colocalized with apoptotic cells. Moreover, anti-TNF-α Ab inhibited the development of diabetes after adoptive transfer. Taken together, our results indicate that IFN-γ/TNF-α synergism is responsible for autoimmune diabetes in vivo as well as β cell apoptosis in vitro and suggest a novel signal transduction in IFN-γ/TNF-α synergism that may have relevance in other autoimmune diseases and synergistic anti-tumor effects of the two cytokines.

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Section: Discussionmentioning

confidence: 99%

IFN-γ/TNF-α Synergism as the Final Effector in Autoimmune Diabetes: A Key Role for STAT1/IFN Regulatory Factor-1 Pathway in Pancreatic β Cell Death

Suk

Kim

et al. 2001

The Journal of Immunology

208

187

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“…However, T cell activation is far more pronounced in the absence of T cell-specific TGF-β signaling than in the absence of Treg cells. Whereas T cells in the pancreatic lymph nodes of Foxp3sf OT-II RIP-mOva mice produce very little cytokine, pancreatic lymph node TβRII-deficient T cells already produce copious amounts of the Th1 cytokine IFN-γ, which is known to promote diabetes development (14,(28)(29)(30). The limited (although significantly increased relative to control OT-II RIPmOva mice) activation of T cells in the draining lymph nodes of Foxp3sf OT-II RIP-mOva mice is consistent with observations in another transgenic model of diabetes, in which Treg cells had little effect on T cell activation in the draining lymph node but were nonetheless important for the prevention of disease development (57).…”

Section: Discussionmentioning

confidence: 99%

“…**P ≤ 0.01. D), a cytokine that is known to play an essential role in diabetes development (14,(28)(29)(30).…”

Section: Enhanced Priming Of Pancreas Draining Lymph Node T Cells In Thementioning

confidence: 99%

Foxp3-independent mechanism by which TGF-β controls peripheral T cell tolerance

Liu

Nixon

et al. 2017

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

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Peripheral T cell tolerance is promoted by the regulatory cytokine TGF-β and Foxp3-expressing Treg cells. However, whether TGF-β and Treg cells are part of the same regulatory module, or exist largely as distinct pathways to repress self-reactive T cells remains incompletely understood. Using a transgenic model of autoimmune diabetes, here we show that ablation of TGF-β receptor II (TβRII) in T cells, but not Foxp3 deficiency, resulted in early-onset diabetes with complete penetrance. The rampant autoimmune disease was associated with enhanced T cell priming and elevated T cell expression of the inflammatory cytokine GM-CSF, concomitant with pancreatic infiltration of inflammatory monocytes that triggered immunopathology. Ablation of the GM-CSF receptor alleviated the monocyte response and inhibited disease development. These findings reveal that TGF-β promotes T cell tolerance primarily via Foxp3-independent mechanisms and prevents autoimmunity in this model by repressing the cross talk between adaptive and innate immune systems.

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“…These observations are consistent with observations in various knockout NOD mice. In IFN-␥-deficient NOD mice, insulitis has been shown, but with a lower incidence of overt diabetes, suggesting that IFN-␥ contributes to the progression of diabetes rather than to the initiation of insulitis (42). On the other hand, IL-2 or IL-2R knockout mice have shown autoimmune lymphoproliferative diseases (43)(44)(45).…”

Section: Role Of Il-12 In Autoimmune Diabetesmentioning

confidence: 99%

Suppression and acceleration of autoimmune diabetes by neutralization of endogenous interleukin-12 in NOD mice.

et al. 2000

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A corpus of evidence suggests that T-helper type 1 (Th1)-dependent cellular immunity plays a pivotal role in the pathogenesis of autoimmune diabetes. This study was intended to find ways to prevent the development of NOD diabetes using a neutralizing anti-interleukin (IL)-12 antibody (C17.8) that inhibits Th1 cell differentiation. When C17.8 was administered from 5 to 30 weeks of age, NOD mice exhibited suppression of both insulitis and diabetes. However, when C17.8 administration ceased at 15 weeks of age, 8 of 13 recipients showed diabetes at 30 weeks of age. These results suggest that IL-12 plays an important role not only in the development of effector cells but also in their activation. In contrast, when C17.8 was injected into 2-week-old female NOD mice for 6 consecutive days, all 16 recipients showed diabetes at 30 weeks of age, whereas 12 of 20 control mice became diabetic. This result suggests that depletion of endogenous IL-12 at a young age results in the enhancement of diabetes. Flow cytometric analysis indicated that activated memory T-cells were present in higher numbers after C17.8 treatment. Transfer of spleen cells from 15-week-old C17.8-treated NOD mice to NOD-scid mice resulted in an earlier onset and a higher incidence of diabetes. Furthermore, administration of C17.8 to 2-week-old NOD mice also resulted in a much earlier onset of diabetes. These results suggest that short-term treatment with anti-IL-12 antibody prohibits IL-2 production at a young age, which may influence the expansion and apoptosis of pathogenic T-cells, resulting in the acceleration of autoimmune diabetes.

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Genetic Absence of γ-Interferon Delays but Does Not Prevent Diabetes in NOD Mice

Cited by 184 publications

References 0 publications

IFN-γ/TNF-α Synergism as the Final Effector in Autoimmune Diabetes: A Key Role for STAT1/IFN Regulatory Factor-1 Pathway in Pancreatic β Cell Death

IFN-γ/TNF-α Synergism as the Final Effector in Autoimmune Diabetes: A Key Role for STAT1/IFN Regulatory Factor-1 Pathway in Pancreatic β Cell Death

Foxp3-independent mechanism by which TGF-β controls peripheral T cell tolerance

Suppression and acceleration of autoimmune diabetes by neutralization of endogenous interleukin-12 in NOD mice.

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