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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

Cellular pro-inflammatory immune responses were heightened when FL was given during accelerated anti-GBM disease.(A) IL-17A+ spots and (B) IFNγ+ spots per 1 million stimulated splenocytes, measured by EliSpot. (C) Total spleen and LN cell number. (D, E) Proportion of CD11c+ cells and pDCs in the spleen and LN. (F) Representative FACS plots of splenocytes stained for CD11c and PDCA-1. (G) Proportion of activated T cells (CD4+CD25+/CD4+) in spleen and LN. (H) Representative FACS plots of pooled LN cells stained for CD4, CD25 and foxp3. (I, J) Proportions of Tregs (CD4+CD25+foxp3+/CD4+) and Teff (CD4+CD25+foxp3-/CD4+) in spleen and LN. Black bars represent PBS treated mice. White bars represent FL treated mice. n = 7 per group. *P<0.05, **P<0.01, ***P<0.001, ****P<0.0001.
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pone.0123118.g006: Cellular pro-inflammatory immune responses were heightened when FL was given during accelerated anti-GBM disease.(A) IL-17A+ spots and (B) IFNγ+ spots per 1 million stimulated splenocytes, measured by EliSpot. (C) Total spleen and LN cell number. (D, E) Proportion of CD11c+ cells and pDCs in the spleen and LN. (F) Representative FACS plots of splenocytes stained for CD11c and PDCA-1. (G) Proportion of activated T cells (CD4+CD25+/CD4+) in spleen and LN. (H) Representative FACS plots of pooled LN cells stained for CD4, CD25 and foxp3. (I, J) Proportions of Tregs (CD4+CD25+foxp3+/CD4+) and Teff (CD4+CD25+foxp3-/CD4+) in spleen and LN. Black bars represent PBS treated mice. White bars represent FL treated mice. n = 7 per group. *P<0.05, **P<0.01, ***P<0.001, ****P<0.0001.

Mentions: Systemic inflammatory immune responses were heightened in the FL treated mice, with significantly increased IL-17A production, and a trend towards enhanced IFNγ production by splenocytes (Fig 6A and 6B). IL-6 concentrations were not different between groups (median with range, PBS 0 [0–12] vs FL 0 [0–14], P = 0.29). IL-12p70, TNF and IL-10 concentrations were undetectable in both groups. Within the spleen and LN, cell numbers were similar between groups, but FL treated mice had significantly increased proportions of CD11c+ cells and reduced proportions of pDCs (Fig 6C–6F). FL treated mice had elevated proportions of activated (CD4+CD25+) T cells and Tregs (CD4+CD25+foxp3+), with a similar proportion of effector T cells (CD4+CD25+foxp3-) within LN, but in the spleen FL treated mice had fewer activated T cells and Teff (Fig 6G–6J). Therefore, FL administration throughout experimental RPGN promoted maturation of DCs towards a conventional DC phenotype. It did not suppress nephritogenic immunity, but rather FL enhanced systemic immunity and T cell activation.


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)

Cellular pro-inflammatory immune responses were heightened when FL was given during accelerated anti-GBM disease.(A) IL-17A+ spots and (B) IFNγ+ spots per 1 million stimulated splenocytes, measured by EliSpot. (C) Total spleen and LN cell number. (D, E) Proportion of CD11c+ cells and pDCs in the spleen and LN. (F) Representative FACS plots of splenocytes stained for CD11c and PDCA-1. (G) Proportion of activated T cells (CD4+CD25+/CD4+) in spleen and LN. (H) Representative FACS plots of pooled LN cells stained for CD4, CD25 and foxp3. (I, J) Proportions of Tregs (CD4+CD25+foxp3+/CD4+) and Teff (CD4+CD25+foxp3-/CD4+) in spleen and LN. Black bars represent PBS treated mice. White bars represent FL treated mice. n = 7 per group. *P<0.05, **P<0.01, ***P<0.001, ****P<0.0001.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0123118.g006: Cellular pro-inflammatory immune responses were heightened when FL was given during accelerated anti-GBM disease.(A) IL-17A+ spots and (B) IFNγ+ spots per 1 million stimulated splenocytes, measured by EliSpot. (C) Total spleen and LN cell number. (D, E) Proportion of CD11c+ cells and pDCs in the spleen and LN. (F) Representative FACS plots of splenocytes stained for CD11c and PDCA-1. (G) Proportion of activated T cells (CD4+CD25+/CD4+) in spleen and LN. (H) Representative FACS plots of pooled LN cells stained for CD4, CD25 and foxp3. (I, J) Proportions of Tregs (CD4+CD25+foxp3+/CD4+) and Teff (CD4+CD25+foxp3-/CD4+) in spleen and LN. Black bars represent PBS treated mice. White bars represent FL treated mice. n = 7 per group. *P<0.05, **P<0.01, ***P<0.001, ****P<0.0001.
Mentions: Systemic inflammatory immune responses were heightened in the FL treated mice, with significantly increased IL-17A production, and a trend towards enhanced IFNγ production by splenocytes (Fig 6A and 6B). IL-6 concentrations were not different between groups (median with range, PBS 0 [0–12] vs FL 0 [0–14], P = 0.29). IL-12p70, TNF and IL-10 concentrations were undetectable in both groups. Within the spleen and LN, cell numbers were similar between groups, but FL treated mice had significantly increased proportions of CD11c+ cells and reduced proportions of pDCs (Fig 6C–6F). FL treated mice had elevated proportions of activated (CD4+CD25+) T cells and Tregs (CD4+CD25+foxp3+), with a similar proportion of effector T cells (CD4+CD25+foxp3-) within LN, but in the spleen FL treated mice had fewer activated T cells and Teff (Fig 6G–6J). Therefore, FL administration throughout experimental RPGN promoted maturation of DCs towards a conventional DC phenotype. It did not suppress nephritogenic immunity, but rather FL enhanced systemic immunity and T cell activation.

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