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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

Effects of FL given during sensitization, but not during the nephritic phase of injury.(A) Experimental design. (B) Serum urea (dotted line represents measured level in non-nephritic WT mice, n = 4). (C) Proteinuria (dotted line represents measured level in non-nephritic WT mice, n = 4). (D, E) Percentage of glomerular crescents and segmental necrosis. (F) Total spleen and LN cell number. (G) Proportion of Tregs in the spleen and LN. (H) Serum mouse anti-sheep IgG antibody concentrations. Black bars represent PBS treated mice. White bars represent FL treated mice. OD, optical density. n = 7 for PBS group and 9 for FL group. *P<0.05, ***P<0.001.
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pone.0123118.g007: Effects of FL given during sensitization, but not during the nephritic phase of injury.(A) Experimental design. (B) Serum urea (dotted line represents measured level in non-nephritic WT mice, n = 4). (C) Proteinuria (dotted line represents measured level in non-nephritic WT mice, n = 4). (D, E) Percentage of glomerular crescents and segmental necrosis. (F) Total spleen and LN cell number. (G) Proportion of Tregs in the spleen and LN. (H) Serum mouse anti-sheep IgG antibody concentrations. Black bars represent PBS treated mice. White bars represent FL treated mice. OD, optical density. n = 7 for PBS group and 9 for FL group. *P<0.05, ***P<0.001.

Mentions: This model of RPGN relies on planting sheep globulin, a foreign antigen, within the glomerulus of sensitized mice. It was possible that exogenous FL, administered at the time of anti-GBM globulin injection, enhanced the maturation and expansion of cDCs in sensitized mice rather than polarizing precursor DCs towards this phenotype. We sought to determine if FL could induce pDCs and enhance Treg populations in steady state conditions and suppress subsequent antigen-specific responses. Therefore, we administered FL before and during the sensitization period (i.e. when DCs were playing a key role in inducing immunity to sheep globulin) but discontinued it at the time nephritis was induced (Fig 7A).


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)

Effects of FL given during sensitization, but not during the nephritic phase of injury.(A) Experimental design. (B) Serum urea (dotted line represents measured level in non-nephritic WT mice, n = 4). (C) Proteinuria (dotted line represents measured level in non-nephritic WT mice, n = 4). (D, E) Percentage of glomerular crescents and segmental necrosis. (F) Total spleen and LN cell number. (G) Proportion of Tregs in the spleen and LN. (H) Serum mouse anti-sheep IgG antibody concentrations. Black bars represent PBS treated mice. White bars represent FL treated mice. OD, optical density. n = 7 for PBS group and 9 for FL group. *P<0.05, ***P<0.001.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4388844&req=5

pone.0123118.g007: Effects of FL given during sensitization, but not during the nephritic phase of injury.(A) Experimental design. (B) Serum urea (dotted line represents measured level in non-nephritic WT mice, n = 4). (C) Proteinuria (dotted line represents measured level in non-nephritic WT mice, n = 4). (D, E) Percentage of glomerular crescents and segmental necrosis. (F) Total spleen and LN cell number. (G) Proportion of Tregs in the spleen and LN. (H) Serum mouse anti-sheep IgG antibody concentrations. Black bars represent PBS treated mice. White bars represent FL treated mice. OD, optical density. n = 7 for PBS group and 9 for FL group. *P<0.05, ***P<0.001.
Mentions: This model of RPGN relies on planting sheep globulin, a foreign antigen, within the glomerulus of sensitized mice. It was possible that exogenous FL, administered at the time of anti-GBM globulin injection, enhanced the maturation and expansion of cDCs in sensitized mice rather than polarizing precursor DCs towards this phenotype. We sought to determine if FL could induce pDCs and enhance Treg populations in steady state conditions and suppress subsequent antigen-specific responses. Therefore, we administered FL before and during the sensitization period (i.e. when DCs were playing a key role in inducing immunity to sheep globulin) but discontinued it at the time nephritis was induced (Fig 7A).

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