Overexpression of Bcl‐2 in T Cells Affects Insulitis in the Nonobese Diabetic Mouse

Rietz, Cecilia; Screpanti, Valentina; Brenden, Nina; Böhme, Jan; Fernández, Carmen

doi:10.1046/j.1365-3083.2003.01244.x

Cited by 7 publications

(9 citation statements)

References 38 publications

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“…Finally, it should be noted that the deficiency in Treg survival might be compounded by an independent genetic defect in Bcl-2 expression in NOD mice (Garchon et al, 1994). In fact, overexpression of Bcl-2 in T cells and B cells alleviated insulitis and conferred diabetes protection (Rietz et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

Central Role of Defective Interleukin-2 Production in the Triggering of Islet Autoimmune Destruction

et al. 2008

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The dynamics of CD4(+) effector T cells (Teff cells) and CD4(+)Foxp3(+) regulatory T cells (Treg cells) during diabetes progression in nonobese diabetic mice was investigated to determine whether an imbalance of Treg cells and Teff cells contributes to the development of type 1 diabetes. Our results demonstrated a progressive decrease in the Treg cell:Teff cell ratio in inflamed islets but not in pancreatic lymph nodes. Intra-islet Treg cells expressed reduced amounts of CD25 and Bcl-2, suggesting that their decline was due to increased apoptosis. Additionally, administration of low-dose interleukin-2 (IL-2) promoted Treg cell survival and protected mice from developing diabetes. Together, these results suggest intra-islet Treg cell dysfunction secondary to defective IL-2 production is a root cause of the progressive breakdown of self-tolerance and the development of diabetes in nonobese diabetic mice.

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Section: Discussionmentioning

confidence: 99%

Central Role of Defective Interleukin-2 Production in the Triggering of Islet Autoimmune Destruction

et al. 2008

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“…It has been shown that over-expression of Bcl-2 in both T and B cells leads to protection from insulitis in NOD mice [52]. There is also clinical support for this concept, since insulin-dependent diabetes mellitus (IDDM) patients show significantly reduced Bcl-2 expression in CD3+ and memory CD4+CD45RO+ populations and have higher levels of spontaneous apoptosis [53].…”

Section: Discussionmentioning

confidence: 99%

IL-21 Limits Peripheral Lymphocyte Numbers through T Cell Homeostatic Mechanisms

Datta

Sarvetnick

2008

PLoS ONE

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BackgroundIL-21, a member of the common γ-chain utilizing family of cytokines, participates in immune and inflammatory processes. In addition, the cytokine has been linked to autoimmunity in humans and rodents.Methodology/Principal FindingsTo investigate the mechanism whereby IL-21 affects the immune system, we investigated its role in T cell homeostasis and autoimmunity in both non-autoimmune C57BL/6 and autoimmune NOD mice. Our data indicate that IL-21R knockout C57BL/6 and NOD mice show increased size of their lymphocyte population and decreased homeostatic proliferation. In addition, our experimental results demonstrate that IL-21 inhibits T cell survival. These data suggest that IL-21 acts to limit the size of the T cell pool. Furthermore, our data suggest IL-21 may contribute to the development of autoimmunity.Conclusions/SignificanceTaken together, our results suggest that IL-21 plays a global role in regulating T cell homeostasis, promoting the continuous adaptation of the T cell lymphoid space.

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“…The histology score index was calculated by dividing the sum of all individual islet scores by the total number of islets evaluated. 51 Statistical analysis. Statistical analysis was performed using the Stata 8.2 (STATA, College Station, TX) software package, and the data collected were expressed as mean ± SEM.…”

Section: Flow Cytometric Analysis Of T-reg Cells In Mil-4-treated Nodmentioning

confidence: 99%

AAV8-mediated Gene Transfer of Interleukin-4 to Endogenous β-Cells Prevents the Onset of Diabetes in NOD Mice

et al. 2008

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We have demonstrated the ability to deliver and express genes specifically in beta-cells for at least 6 months, using a murine insulin promoter (mIP) in a double-stranded, self-complementary AAV vector (dsAAV8-mIP). In this study, we evaluated the effects of dsAAV8-mIP-mediated delivery of interleukin 4 (mIL-4) to endogenous beta-cells in nonobese diabetic (NOD) mice. In 4-week-old NOD mice, the extent of gene transfer and expression in endogenous beta-cells after ip delivery of dsAAV8-mIP-enhanced green fluorescent protein (eGFP) was comparable to normal BALB/C mice. Further, after IP delivery of dsAAV8-mIP-IL4, expression of mIL-4 was detected in islets isolated from the treated mice and cultured. AAV8-mIP-mediated gene expression of mIL-4 in endogenous beta- cells of 4- and 8-week-old NOD mice prevented the onset of hyperglycemia in NOD mice and reduced the severity of insulitis. Moreover, expression of mIL-4 also maintained the level of CD4(+)CD25(+)FoxP3(+) cells, and adoptive transfer of splenocytes from nondiabetic dsAAV8-mIP-IL-4 mice to NODscid mice was able to block the diabetes induced by splenocytes co-adoptively transferred from nondiabetic dsAAV-mIP-eGFP mice. Taken together, these results demonstrate that local expression of mIL-4 in islets prevents islet destruction and blocks autoimmunity, partly through regulation of T-cell function.

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Overexpression of Bcl‐2 in T Cells Affects Insulitis in the Nonobese Diabetic Mouse

Cited by 7 publications

References 38 publications

Central Role of Defective Interleukin-2 Production in the Triggering of Islet Autoimmune Destruction

Central Role of Defective Interleukin-2 Production in the Triggering of Islet Autoimmune Destruction

IL-21 Limits Peripheral Lymphocyte Numbers through T Cell Homeostatic Mechanisms

AAV8-mediated Gene Transfer of Interleukin-4 to Endogenous β-Cells Prevents the Onset of Diabetes in NOD Mice

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