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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

FL therapy throughout accelerated anti-GBM disease did not protect mice from nephritis.(A) Experimental design. (B) Proteinuria. (C) Percentage of glomerular crescents and (D) glomeruli with segmental necrosis. (E) Representative images of glomeruli from PBS and FL treated mice taken at high power (400x, PAS stain). (F–H) gcs, periglomerular and interstitial hpf CD11c+ immunofluorescence assessed by fluorescent microscopy of renal sections. (I) Representative images of CD11c+ immunofluorescent staining within the interstitial, glomerular and periglomerular regions. Black bars represent PBS treated mice. White bars represent FL treated mice. AU, arbitrary units; gcs, glomerular cross section; hpf, high-powered field. n = 7 per group. *P<0.05.
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pone.0123118.g005: FL therapy throughout accelerated anti-GBM disease did not protect mice from nephritis.(A) Experimental design. (B) Proteinuria. (C) Percentage of glomerular crescents and (D) glomeruli with segmental necrosis. (E) Representative images of glomeruli from PBS and FL treated mice taken at high power (400x, PAS stain). (F–H) gcs, periglomerular and interstitial hpf CD11c+ immunofluorescence assessed by fluorescent microscopy of renal sections. (I) Representative images of CD11c+ immunofluorescent staining within the interstitial, glomerular and periglomerular regions. Black bars represent PBS treated mice. White bars represent FL treated mice. AU, arbitrary units; gcs, glomerular cross section; hpf, high-powered field. n = 7 per group. *P<0.05.

Mentions: When FL treatment commenced on the day mice were sensitized to sheep globulin and continued through the course of disease (Fig 4A), more FL treated animals unexpectedly developed signs of renal failure, and met criteria for humane euthanasia, compared to PBS treated controls, occurring after sheep anti-mouse GBM globulin administration during nephritis (Fig 4B); the experiment was terminated early at day 10 of the model. A repeat experiment was performed, with animals being euthanized at day 9 (five days after anti-GBM administration; Fig 5A). Mice in both groups sustained significant functional renal injury (serum urea; PBS 121±16 vs FL 126±10 mmol/L, P = 0.78), with comparable proteinuria and histological damage, marked by widespread glomerular segmental necrosis (Fig 5B–5E). FL treated mice had enhanced interstitial neutrophil recruitment compared to controls (Table 2). Renal CD11c+ cells were increased within glomeruli of FL treated mice, with a trend to increase in periglomerular and interstitial regions (Fig 5F–5I).


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)

FL therapy throughout accelerated anti-GBM disease did not protect mice from nephritis.(A) Experimental design. (B) Proteinuria. (C) Percentage of glomerular crescents and (D) glomeruli with segmental necrosis. (E) Representative images of glomeruli from PBS and FL treated mice taken at high power (400x, PAS stain). (F–H) gcs, periglomerular and interstitial hpf CD11c+ immunofluorescence assessed by fluorescent microscopy of renal sections. (I) Representative images of CD11c+ immunofluorescent staining within the interstitial, glomerular and periglomerular regions. Black bars represent PBS treated mice. White bars represent FL treated mice. AU, arbitrary units; gcs, glomerular cross section; hpf, high-powered field. n = 7 per group. *P<0.05.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0123118.g005: FL therapy throughout accelerated anti-GBM disease did not protect mice from nephritis.(A) Experimental design. (B) Proteinuria. (C) Percentage of glomerular crescents and (D) glomeruli with segmental necrosis. (E) Representative images of glomeruli from PBS and FL treated mice taken at high power (400x, PAS stain). (F–H) gcs, periglomerular and interstitial hpf CD11c+ immunofluorescence assessed by fluorescent microscopy of renal sections. (I) Representative images of CD11c+ immunofluorescent staining within the interstitial, glomerular and periglomerular regions. Black bars represent PBS treated mice. White bars represent FL treated mice. AU, arbitrary units; gcs, glomerular cross section; hpf, high-powered field. n = 7 per group. *P<0.05.
Mentions: When FL treatment commenced on the day mice were sensitized to sheep globulin and continued through the course of disease (Fig 4A), more FL treated animals unexpectedly developed signs of renal failure, and met criteria for humane euthanasia, compared to PBS treated controls, occurring after sheep anti-mouse GBM globulin administration during nephritis (Fig 4B); the experiment was terminated early at day 10 of the model. A repeat experiment was performed, with animals being euthanized at day 9 (five days after anti-GBM administration; Fig 5A). Mice in both groups sustained significant functional renal injury (serum urea; PBS 121±16 vs FL 126±10 mmol/L, P = 0.78), with comparable proteinuria and histological damage, marked by widespread glomerular segmental necrosis (Fig 5B–5E). FL treated mice had enhanced interstitial neutrophil recruitment compared to controls (Table 2). Renal CD11c+ cells were increased within glomeruli of FL treated mice, with a trend to increase in periglomerular and interstitial regions (Fig 5F–5I).

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