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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 administered before accelerated autologous phase anti-GBM disease did not protect against nephritis, but altered systemic immunity.(A) Proteinuria (dotted line represents measured level in non-nephritic WT mice, n = 4). (B) Serum urea (dotted line represents measured level in non-nephritic WT mice, n = 4). (C) Proportions of glomeruli with crescents and (D) glomerular segmental necrosis. (E) Representative images of glomeruli from PBS and FL treated mice taken at high power (400x, PAS stain). (F) Total spleen and LN cell number. (G) Proportion of CD11c+ cells from leukocytes in spleen and LN. (H) Proportion of pDCs in spleen and LN. (I) Serum mouse anti-sheep IgG antibody levels. Black bars represent PBS treated mice. White bars represent FL treated mice. OD, optical density. n = 6 per group. *P<0.05.
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pone.0123118.g003: FL administered before accelerated autologous phase anti-GBM disease did not protect against nephritis, but altered systemic immunity.(A) Proteinuria (dotted line represents measured level in non-nephritic WT mice, n = 4). (B) Serum urea (dotted line represents measured level in non-nephritic WT mice, n = 4). (C) Proportions of glomeruli with crescents and (D) glomerular segmental necrosis. (E) Representative images of glomeruli from PBS and FL treated mice taken at high power (400x, PAS stain). (F) Total spleen and LN cell number. (G) Proportion of CD11c+ cells from leukocytes in spleen and LN. (H) Proportion of pDCs in spleen and LN. (I) Serum mouse anti-sheep IgG antibody levels. Black bars represent PBS treated mice. White bars represent FL treated mice. OD, optical density. n = 6 per group. *P<0.05.

Mentions: When FL or PBS was administered for 10 days before the model of RPGN (with treatment ending the day before mice were immunized with sheep globulin), injury was similar in both groups of mice. No significant differences in renal functional injury (proteinuria or urea; Fig 3A and 3B) or histological damage (glomerular crescents or segmental necrosis; Fig 3C–3E) were found. While the total number of splenocytes or LN cells was not different between groups, the proportion of splenic CD11c+ cells was reduced in FL treated mice (Fig 3F and 3G), but unaltered in the LN between groups. There was no difference in the proportion of pDCs (Fig 3H), nor was there a difference in the proportion of activated T cells (CD4+CD25+/CD4+ cells) in the spleen and LN between the two groups (spleen PBS 4.4±0.4 vs FL 5.5±0.4%, P = 0.12; LN PBS 34.1±3.6 vs 35.9±2.8%, P = 0.7). With respect to cellular immune responses, FL treated mice had reduced IL-17A levels in sheep globulin stimulated splenocyte supernatant compared to controls, but no differences were found in IFNγ, IL-4 or IL-10 concentrations (Table 1); TNF, IL-12p70 and IL-6 concentrations were below the threshold for detection in both groups. FL treated animals had a trend towards lower serum mouse anti-sheep immunoglobulin titres (Fig 3I). Therefore, although FL did not protect mice when given prior to the induction of crescentic GN, some elements of cellular and humoral immune responses were attenuated by FL therapy, suggesting that FL might alter renal injury if delivered throughout the entire course of this disease model.


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 administered before accelerated autologous phase anti-GBM disease did not protect against nephritis, but altered systemic immunity.(A) Proteinuria (dotted line represents measured level in non-nephritic WT mice, n = 4). (B) Serum urea (dotted line represents measured level in non-nephritic WT mice, n = 4). (C) Proportions of glomeruli with crescents and (D) glomerular segmental necrosis. (E) Representative images of glomeruli from PBS and FL treated mice taken at high power (400x, PAS stain). (F) Total spleen and LN cell number. (G) Proportion of CD11c+ cells from leukocytes in spleen and LN. (H) Proportion of pDCs in spleen and LN. (I) Serum mouse anti-sheep IgG antibody levels. Black bars represent PBS treated mice. White bars represent FL treated mice. OD, optical density. n = 6 per group. *P<0.05.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4388844&req=5

pone.0123118.g003: FL administered before accelerated autologous phase anti-GBM disease did not protect against nephritis, but altered systemic immunity.(A) Proteinuria (dotted line represents measured level in non-nephritic WT mice, n = 4). (B) Serum urea (dotted line represents measured level in non-nephritic WT mice, n = 4). (C) Proportions of glomeruli with crescents and (D) glomerular segmental necrosis. (E) Representative images of glomeruli from PBS and FL treated mice taken at high power (400x, PAS stain). (F) Total spleen and LN cell number. (G) Proportion of CD11c+ cells from leukocytes in spleen and LN. (H) Proportion of pDCs in spleen and LN. (I) Serum mouse anti-sheep IgG antibody levels. Black bars represent PBS treated mice. White bars represent FL treated mice. OD, optical density. n = 6 per group. *P<0.05.
Mentions: When FL or PBS was administered for 10 days before the model of RPGN (with treatment ending the day before mice were immunized with sheep globulin), injury was similar in both groups of mice. No significant differences in renal functional injury (proteinuria or urea; Fig 3A and 3B) or histological damage (glomerular crescents or segmental necrosis; Fig 3C–3E) were found. While the total number of splenocytes or LN cells was not different between groups, the proportion of splenic CD11c+ cells was reduced in FL treated mice (Fig 3F and 3G), but unaltered in the LN between groups. There was no difference in the proportion of pDCs (Fig 3H), nor was there a difference in the proportion of activated T cells (CD4+CD25+/CD4+ cells) in the spleen and LN between the two groups (spleen PBS 4.4±0.4 vs FL 5.5±0.4%, P = 0.12; LN PBS 34.1±3.6 vs 35.9±2.8%, P = 0.7). With respect to cellular immune responses, FL treated mice had reduced IL-17A levels in sheep globulin stimulated splenocyte supernatant compared to controls, but no differences were found in IFNγ, IL-4 or IL-10 concentrations (Table 1); TNF, IL-12p70 and IL-6 concentrations were below the threshold for detection in both groups. FL treated animals had a trend towards lower serum mouse anti-sheep immunoglobulin titres (Fig 3I). Therefore, although FL did not protect mice when given prior to the induction of crescentic GN, some elements of cellular and humoral immune responses were attenuated by FL therapy, suggesting that FL might alter renal injury if delivered throughout the entire course of this disease model.

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