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FMS-like tyrosine kinase 3 ligand treatment does not ameliorate experimental rapidly progressive glomerulonephritis.

Ghali JR, O'Sullivan KM, Eggenhuizen PJ, Holdsworth SR, Kitching AR - PLoS ONE (2015)

Bottom Line: FL increased regulatory T cell and plasmacytoid dendritic cell proportions within spleen and lymph nodes.Systemic immune responses showed increased IL-17A production from splenocytes, with more CD11c+ cells, but reduced plasmacytoid dendritic cell proportions in spleen and lymph nodes, despite increased regulatory T cell proportions.Under homeostatic conditions, FL expanded regulatory T cell and plasmacytoid dendritic cell populations, but FL enhanced systemic inflammatory responses and conventional dendritic cell populations when given during experimental glomerulonephritis, suggesting selective attempts to suppress pathogenic immunity by dendritic cell manipulation may be harmful.

View Article: PubMed Central - PubMed

Affiliation: Centre for Inflammatory Diseases, Department of Medicine, Monash University, Clayton, Victoria, Australia; Department of Nephrology, Monash Health, Clayton, Victoria, Australia.

ABSTRACT
Fms-like tyrosine kinase 3-ligand (FL) is a growth factor that may expand dendritic cell and regulatory T cell populations. We hypothesised that FL-induced regulatory T cells would protect mice from experimental rapidly progressive glomerulonephritis. To determine if FL was able to enhance regulatory T cell populations, C57BL/6 mice received 10 days of daily intraperitoneal injections of either FL or phosphate buffered saline. To induce accelerated autologous-phase anti-mouse glomerular basement membrane glomerulonephritis, mice were sensitized to sheep globulin 4 days prior to the induction of glomerulonephritis with sheep anti-mouse glomerular basement membrane globulin, and experiments ended 10 days later. FL was administered before, throughout and during the sensitization phase of this glomerulonephritis model. Renal disease and systemic immunity to the nephritogenic antigen were assessed. FL increased regulatory T cell and plasmacytoid dendritic cell proportions within spleen and lymph nodes. FL administration prior to glomerulonephritis did not protect mice from renal injury. When FL was given throughout the model, FL treated mice had reduced survival, with more interstitial neutrophils and glomerular CD11c+ cells than controls. Systemic immune responses showed increased IL-17A production from splenocytes, with more CD11c+ cells, but reduced plasmacytoid dendritic cell proportions in spleen and lymph nodes, despite increased regulatory T cell proportions. Under homeostatic conditions, FL expanded regulatory T cell and plasmacytoid dendritic cell populations, but FL enhanced systemic inflammatory responses and conventional dendritic cell populations when given during experimental glomerulonephritis, suggesting selective attempts to suppress pathogenic immunity by dendritic cell manipulation may be harmful.

No MeSH data available.


Related in: MedlinePlus

The effects of 10 days of intraperitoneal FL on DC and Treg populations.(A) Experimental design, where FL or PBS was administered intraperitoneally to mice for daily for 10 days. (B) Total spleen and pooled LN cell number. (C) Representative FACS plots showing proportions of pDCs (CD11c+PDCA-1+ cells) in the spleen, gating on all CD11c+ leukocytes. (D) Proportions of CD11c+ cells in the spleen and LN. (E) Proportions of pDCs in the spleen and LN. (F) Representative FACS plots showing Tregs in the spleen, gating on lymphocytes, staining for CD4+ and foxp3+ cells. (G) Proportion of Tregs in the spleen and LN. Black bars represent PBS treated mice. White bars represent FL treated mice. n = 4 per group. *P<0.05, **P<0.01, ***P<0.001.
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pone.0123118.g001: The effects of 10 days of intraperitoneal FL on DC and Treg populations.(A) Experimental design, where FL or PBS was administered intraperitoneally to mice for daily for 10 days. (B) Total spleen and pooled LN cell number. (C) Representative FACS plots showing proportions of pDCs (CD11c+PDCA-1+ cells) in the spleen, gating on all CD11c+ leukocytes. (D) Proportions of CD11c+ cells in the spleen and LN. (E) Proportions of pDCs in the spleen and LN. (F) Representative FACS plots showing Tregs in the spleen, gating on lymphocytes, staining for CD4+ and foxp3+ cells. (G) Proportion of Tregs in the spleen and LN. Black bars represent PBS treated mice. White bars represent FL treated mice. n = 4 per group. *P<0.05, **P<0.01, ***P<0.001.

Mentions: Daily administration of FL for 10 days (Fig 1A) macroscopically increased spleen size and the size of all LN groups. When quantified, there were increased splenic cell numbers, with a trend towards increased cell numbers in pooled LN (Fig 1B). CD11c+ cells were also increased in the spleen and LN after FL administration (Fig 1C and 1D). Proportions of pDCs (CD11c+PDCA-1+/CD11c+ cells) were significantly elevated in the spleen, with a trend towards increase in the LN (Fig 1C and 1E). The proportion of Tregs (CD4+foxp3+/CD4+ cells) in FL treated animals was significantly increased (Fig 1F and 1G).


FMS-like tyrosine kinase 3 ligand treatment does not ameliorate experimental rapidly progressive glomerulonephritis.

Ghali JR, O'Sullivan KM, Eggenhuizen PJ, Holdsworth SR, Kitching AR - PLoS ONE (2015)

The effects of 10 days of intraperitoneal FL on DC and Treg populations.(A) Experimental design, where FL or PBS was administered intraperitoneally to mice for daily for 10 days. (B) Total spleen and pooled LN cell number. (C) Representative FACS plots showing proportions of pDCs (CD11c+PDCA-1+ cells) in the spleen, gating on all CD11c+ leukocytes. (D) Proportions of CD11c+ cells in the spleen and LN. (E) Proportions of pDCs in the spleen and LN. (F) Representative FACS plots showing Tregs in the spleen, gating on lymphocytes, staining for CD4+ and foxp3+ cells. (G) Proportion of Tregs in the spleen and LN. Black bars represent PBS treated mice. White bars represent FL treated mice. n = 4 per group. *P<0.05, **P<0.01, ***P<0.001.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4388844&req=5

pone.0123118.g001: The effects of 10 days of intraperitoneal FL on DC and Treg populations.(A) Experimental design, where FL or PBS was administered intraperitoneally to mice for daily for 10 days. (B) Total spleen and pooled LN cell number. (C) Representative FACS plots showing proportions of pDCs (CD11c+PDCA-1+ cells) in the spleen, gating on all CD11c+ leukocytes. (D) Proportions of CD11c+ cells in the spleen and LN. (E) Proportions of pDCs in the spleen and LN. (F) Representative FACS plots showing Tregs in the spleen, gating on lymphocytes, staining for CD4+ and foxp3+ cells. (G) Proportion of Tregs in the spleen and LN. Black bars represent PBS treated mice. White bars represent FL treated mice. n = 4 per group. *P<0.05, **P<0.01, ***P<0.001.
Mentions: Daily administration of FL for 10 days (Fig 1A) macroscopically increased spleen size and the size of all LN groups. When quantified, there were increased splenic cell numbers, with a trend towards increased cell numbers in pooled LN (Fig 1B). CD11c+ cells were also increased in the spleen and LN after FL administration (Fig 1C and 1D). Proportions of pDCs (CD11c+PDCA-1+/CD11c+ cells) were significantly elevated in the spleen, with a trend towards increase in the LN (Fig 1C and 1E). The proportion of Tregs (CD4+foxp3+/CD4+ cells) in FL treated animals was significantly increased (Fig 1F and 1G).

Bottom Line: FL increased regulatory T cell and plasmacytoid dendritic cell proportions within spleen and lymph nodes.Systemic immune responses showed increased IL-17A production from splenocytes, with more CD11c+ cells, but reduced plasmacytoid dendritic cell proportions in spleen and lymph nodes, despite increased regulatory T cell proportions.Under homeostatic conditions, FL expanded regulatory T cell and plasmacytoid dendritic cell populations, but FL enhanced systemic inflammatory responses and conventional dendritic cell populations when given during experimental glomerulonephritis, suggesting selective attempts to suppress pathogenic immunity by dendritic cell manipulation may be harmful.

View Article: PubMed Central - PubMed

Affiliation: Centre for Inflammatory Diseases, Department of Medicine, Monash University, Clayton, Victoria, Australia; Department of Nephrology, Monash Health, Clayton, Victoria, Australia.

ABSTRACT
Fms-like tyrosine kinase 3-ligand (FL) is a growth factor that may expand dendritic cell and regulatory T cell populations. We hypothesised that FL-induced regulatory T cells would protect mice from experimental rapidly progressive glomerulonephritis. To determine if FL was able to enhance regulatory T cell populations, C57BL/6 mice received 10 days of daily intraperitoneal injections of either FL or phosphate buffered saline. To induce accelerated autologous-phase anti-mouse glomerular basement membrane glomerulonephritis, mice were sensitized to sheep globulin 4 days prior to the induction of glomerulonephritis with sheep anti-mouse glomerular basement membrane globulin, and experiments ended 10 days later. FL was administered before, throughout and during the sensitization phase of this glomerulonephritis model. Renal disease and systemic immunity to the nephritogenic antigen were assessed. FL increased regulatory T cell and plasmacytoid dendritic cell proportions within spleen and lymph nodes. FL administration prior to glomerulonephritis did not protect mice from renal injury. When FL was given throughout the model, FL treated mice had reduced survival, with more interstitial neutrophils and glomerular CD11c+ cells than controls. Systemic immune responses showed increased IL-17A production from splenocytes, with more CD11c+ cells, but reduced plasmacytoid dendritic cell proportions in spleen and lymph nodes, despite increased regulatory T cell proportions. Under homeostatic conditions, FL expanded regulatory T cell and plasmacytoid dendritic cell populations, but FL enhanced systemic inflammatory responses and conventional dendritic cell populations when given during experimental glomerulonephritis, suggesting selective attempts to suppress pathogenic immunity by dendritic cell manipulation may be harmful.

No MeSH data available.


Related in: MedlinePlus