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Potential role of regulatory T cells in reversing obesity-linked insulin resistance and diabetic nephropathy.

Eller K, Kirsch A, Wolf AM, Sopper S, Tagwerker A, Stanzl U, Wolf D, Patsch W, Rosenkranz AR, Eller P - Diabetes (2011)

Bottom Line: Obese patients with insulin resistance displayed significantly decreased natural Tregs but an increase in adaptive Tregs in their visceral adipose tissue as compared with lean control subjects.Conversely, adoptive transfer of CD4(+)FoxP3(+) Tregs significantly improved insulin sensitivity and diabetic nephropathy.Accordingly, there was increased mRNA expression of FoxP3 as well as less abundant proinflammatory CD8(+)CD69(+) T cells in visceral adipose tissue and kidneys of Treg-treated animals.

View Article: PubMed Central - PubMed

Affiliation: Clinical Division of Nephrology, Department of Internal Medicine, Medical University Graz, Graz, Austria. kathrin.eller@medunigraz.at

ABSTRACT

Objective: To assess the potential role of FoxP3-expressing regulatory T cells (Tregs) in reversing obesity-linked insulin resistance and diabetic nephropathy in rodent models and humans.

Research design and methods: To characterize the role of Tregs in insulin resistance, human visceral adipose tissue was first evaluated for Treg infiltration and second, the db/db mouse model was evaluated.

Results: Obese patients with insulin resistance displayed significantly decreased natural Tregs but an increase in adaptive Tregs in their visceral adipose tissue as compared with lean control subjects. To further evaluate the pathogenic role of Tregs in insulin resistance, the db/db mouse model was used. Treg depletion using an anti-CD25 monoclonal antibody enhanced insulin resistance as shown by increased fasting blood glucose levels as well as an impaired insulin sensitivity. Moreover, Treg-depleted db/db mice developed increased signs of diabetic nephropathy, such as albuminuria and glomerular hyperfiltration. This was paralleled by a proinflammatory milieu in both murine visceral adipose tissue and the kidney. Conversely, adoptive transfer of CD4(+)FoxP3(+) Tregs significantly improved insulin sensitivity and diabetic nephropathy. Accordingly, there was increased mRNA expression of FoxP3 as well as less abundant proinflammatory CD8(+)CD69(+) T cells in visceral adipose tissue and kidneys of Treg-treated animals.

Conclusions: Data suggest a potential therapeutic value of Tregs to improve insulin resistance and end organ damage in type 2 diabetes by limiting the proinflammatory milieu.

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Treg treatment improves diabetic nephropathy. Db/db mice were uninephrectomized at the age of 6 weeks and followed for 56 days. One group intravenously received FACS-sorted CD4+FoxP3+ Tregs every 14 days (gray bar), whereas control animals received CD4+FoxP3− T cells (black bar). A: The albumin-to-creatinine ratio was evaluated in the urine every 14 days. B and C: After 56 days, kidneys were harvested and the glomerular diameter was morphologically determined (n = 4 per group) (B), and kidney sections were stained for the infiltration of CD8+ T cells (n = 8 per group) (C). Hpf, high-power field. D: The cytokine response in the kidney was evaluated by real-time PCR (n = 8 per group). The fold increase to the mean expression of controls is provided. Pooled data of two independent experiments are shown. *P < 0.05.
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Figure 7: Treg treatment improves diabetic nephropathy. Db/db mice were uninephrectomized at the age of 6 weeks and followed for 56 days. One group intravenously received FACS-sorted CD4+FoxP3+ Tregs every 14 days (gray bar), whereas control animals received CD4+FoxP3− T cells (black bar). A: The albumin-to-creatinine ratio was evaluated in the urine every 14 days. B and C: After 56 days, kidneys were harvested and the glomerular diameter was morphologically determined (n = 4 per group) (B), and kidney sections were stained for the infiltration of CD8+ T cells (n = 8 per group) (C). Hpf, high-power field. D: The cytokine response in the kidney was evaluated by real-time PCR (n = 8 per group). The fold increase to the mean expression of controls is provided. Pooled data of two independent experiments are shown. *P < 0.05.

Mentions: Adoptive transfer of Treg significantly decreased urinary albumin-to-creatinine ratio in db/db mice when compared with respective controls on days 42 and 56 after uninephrectomy (Fig. 7A). In addition, the glomerular diameter, which reflects hyperfiltration, was also significantly decreased in kidneys of Treg-treated mice (Fig. 7B). In line with data from mVAT T-cell infiltration, CD8+ T cells were significantly less abundant in the kidneys of Treg-injected db/db mice (Fig. 7C), whereas the infiltration of CD4+ T cells and macrophages was not affected (data not shown). Despite a trend toward higher expression of the proinflammatory Th1 markers IFN-γ, IL-6, and TNF-α in kidneys of Treg-treated db/db mice, there was a predominant and statistically significant effect on the expression of the anti-inflammatory markers Gata-3, IL-10, and FoxP3 (Fig. 7D). Of note, we were not able to detect adoptively transferred GFP+ Tregs in harvested spleens, livers, kidneys, mSAT, and mVAT of uninephrectomized db/db mice on day 56 (i.e., 14 days after the final Treg-transfer) using either flow cytometry or a highly sensitive PCR for GFP (data not shown).


Potential role of regulatory T cells in reversing obesity-linked insulin resistance and diabetic nephropathy.

Eller K, Kirsch A, Wolf AM, Sopper S, Tagwerker A, Stanzl U, Wolf D, Patsch W, Rosenkranz AR, Eller P - Diabetes (2011)

Treg treatment improves diabetic nephropathy. Db/db mice were uninephrectomized at the age of 6 weeks and followed for 56 days. One group intravenously received FACS-sorted CD4+FoxP3+ Tregs every 14 days (gray bar), whereas control animals received CD4+FoxP3− T cells (black bar). A: The albumin-to-creatinine ratio was evaluated in the urine every 14 days. B and C: After 56 days, kidneys were harvested and the glomerular diameter was morphologically determined (n = 4 per group) (B), and kidney sections were stained for the infiltration of CD8+ T cells (n = 8 per group) (C). Hpf, high-power field. D: The cytokine response in the kidney was evaluated by real-time PCR (n = 8 per group). The fold increase to the mean expression of controls is provided. Pooled data of two independent experiments are shown. *P < 0.05.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC3198056&req=5

Figure 7: Treg treatment improves diabetic nephropathy. Db/db mice were uninephrectomized at the age of 6 weeks and followed for 56 days. One group intravenously received FACS-sorted CD4+FoxP3+ Tregs every 14 days (gray bar), whereas control animals received CD4+FoxP3− T cells (black bar). A: The albumin-to-creatinine ratio was evaluated in the urine every 14 days. B and C: After 56 days, kidneys were harvested and the glomerular diameter was morphologically determined (n = 4 per group) (B), and kidney sections were stained for the infiltration of CD8+ T cells (n = 8 per group) (C). Hpf, high-power field. D: The cytokine response in the kidney was evaluated by real-time PCR (n = 8 per group). The fold increase to the mean expression of controls is provided. Pooled data of two independent experiments are shown. *P < 0.05.
Mentions: Adoptive transfer of Treg significantly decreased urinary albumin-to-creatinine ratio in db/db mice when compared with respective controls on days 42 and 56 after uninephrectomy (Fig. 7A). In addition, the glomerular diameter, which reflects hyperfiltration, was also significantly decreased in kidneys of Treg-treated mice (Fig. 7B). In line with data from mVAT T-cell infiltration, CD8+ T cells were significantly less abundant in the kidneys of Treg-injected db/db mice (Fig. 7C), whereas the infiltration of CD4+ T cells and macrophages was not affected (data not shown). Despite a trend toward higher expression of the proinflammatory Th1 markers IFN-γ, IL-6, and TNF-α in kidneys of Treg-treated db/db mice, there was a predominant and statistically significant effect on the expression of the anti-inflammatory markers Gata-3, IL-10, and FoxP3 (Fig. 7D). Of note, we were not able to detect adoptively transferred GFP+ Tregs in harvested spleens, livers, kidneys, mSAT, and mVAT of uninephrectomized db/db mice on day 56 (i.e., 14 days after the final Treg-transfer) using either flow cytometry or a highly sensitive PCR for GFP (data not shown).

Bottom Line: Obese patients with insulin resistance displayed significantly decreased natural Tregs but an increase in adaptive Tregs in their visceral adipose tissue as compared with lean control subjects.Conversely, adoptive transfer of CD4(+)FoxP3(+) Tregs significantly improved insulin sensitivity and diabetic nephropathy.Accordingly, there was increased mRNA expression of FoxP3 as well as less abundant proinflammatory CD8(+)CD69(+) T cells in visceral adipose tissue and kidneys of Treg-treated animals.

View Article: PubMed Central - PubMed

Affiliation: Clinical Division of Nephrology, Department of Internal Medicine, Medical University Graz, Graz, Austria. kathrin.eller@medunigraz.at

ABSTRACT

Objective: To assess the potential role of FoxP3-expressing regulatory T cells (Tregs) in reversing obesity-linked insulin resistance and diabetic nephropathy in rodent models and humans.

Research design and methods: To characterize the role of Tregs in insulin resistance, human visceral adipose tissue was first evaluated for Treg infiltration and second, the db/db mouse model was evaluated.

Results: Obese patients with insulin resistance displayed significantly decreased natural Tregs but an increase in adaptive Tregs in their visceral adipose tissue as compared with lean control subjects. To further evaluate the pathogenic role of Tregs in insulin resistance, the db/db mouse model was used. Treg depletion using an anti-CD25 monoclonal antibody enhanced insulin resistance as shown by increased fasting blood glucose levels as well as an impaired insulin sensitivity. Moreover, Treg-depleted db/db mice developed increased signs of diabetic nephropathy, such as albuminuria and glomerular hyperfiltration. This was paralleled by a proinflammatory milieu in both murine visceral adipose tissue and the kidney. Conversely, adoptive transfer of CD4(+)FoxP3(+) Tregs significantly improved insulin sensitivity and diabetic nephropathy. Accordingly, there was increased mRNA expression of FoxP3 as well as less abundant proinflammatory CD8(+)CD69(+) T cells in visceral adipose tissue and kidneys of Treg-treated animals.

Conclusions: Data suggest a potential therapeutic value of Tregs to improve insulin resistance and end organ damage in type 2 diabetes by limiting the proinflammatory milieu.

Show MeSH
Related in: MedlinePlus