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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 expands pDCs but increases delayed type hypersensitivity four days after sensitization to sheep globulin.(A) Experimental design. (B, C) Total spleen and LN cell number 4 and 10 days after sensitization, respectively. (D, E) Proportion of pDCs in the spleen and LN 4 and 10 days post-sensitization to sheep globulin respectively. (F, G) Footpad swelling in mice 4 and 10 days post-sensitization to sheep globulin, respectively. Black bars represent PBS treated mice. White bars represent FL treated mice. n = 4 per group. *P<0.05, **P<0.01.
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pone.0123118.g002: FL therapy expands pDCs but increases delayed type hypersensitivity four days after sensitization to sheep globulin.(A) Experimental design. (B, C) Total spleen and LN cell number 4 and 10 days after sensitization, respectively. (D, E) Proportion of pDCs in the spleen and LN 4 and 10 days post-sensitization to sheep globulin respectively. (F, G) Footpad swelling in mice 4 and 10 days post-sensitization to sheep globulin, respectively. Black bars represent PBS treated mice. White bars represent FL treated mice. n = 4 per group. *P<0.05, **P<0.01.

Mentions: To determine if increased populations of pDCs and Tregs induced by FL protected mice from generating effector T cell responses, PBS or FL was administered to mice for 10 days, then mice were sensitized to sheep globulin. Mice were then culled 4 or 10 days after sensitization (Fig 2A). At 4 and 10 days post-sensitization, the numbers of splenocytes and LN cells were not different between PBS and FL treated mice (Fig 2B and 2C). Four days after sensitization to sheep globulin, the proportion of CD11c+ cells remained elevated in the LN, but not the spleen of FL treated mice (spleen PBS 20.9±2.5 vs FL 19.4±2.6%, P = 0.7; LN PBS 6.6±0.3 vs FL 9.6±0.4%, P<0.005). FL treated mice had higher proportions of pDCs in spleen and LN (Fig 2D), Ten days after sensitization to sheep globulin, FL treated mice had a reduced proportion of CD11c+ cells in the LN (spleen PBS 4.3±2.2 vs FL 2.4±0.1%, P = 0.44; LN PBS 1.2±0.03 vs FL 0.9±0.02%, P<0.001), but there was no longer any detectable difference in pDC proportions (Fig 2E). No significant differences in Treg proportions were identified four days after sheep globulin sensitization between mice that had been treated with PBS or FL (spleen PBS 7.2±0.8 vs FL 8.6±0.3%, P = 0.16; LN PBS 8.6±0.1 vs FL 9.5±0.5%, P = 0.11). Four days after sheep globulin sensitisation, FL mice developed increased dermal DTH to sheep globulin, suggesting elevated pDC populations did not suppress antigen-specific immunity, but rather enhanced effector T cell function (Fig 2F). When mice were challenged with sheep globulin 10 days after sensitization, DTH was present to a similar degree in PBS and FL treated groups (Fig 2G).


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 expands pDCs but increases delayed type hypersensitivity four days after sensitization to sheep globulin.(A) Experimental design. (B, C) Total spleen and LN cell number 4 and 10 days after sensitization, respectively. (D, E) Proportion of pDCs in the spleen and LN 4 and 10 days post-sensitization to sheep globulin respectively. (F, G) Footpad swelling in mice 4 and 10 days post-sensitization to sheep globulin, respectively. Black bars represent PBS treated mice. White bars represent FL treated mice. n = 4 per group. *P<0.05, **P<0.01.
© Copyright Policy
Related In: Results  -  Collection

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

pone.0123118.g002: FL therapy expands pDCs but increases delayed type hypersensitivity four days after sensitization to sheep globulin.(A) Experimental design. (B, C) Total spleen and LN cell number 4 and 10 days after sensitization, respectively. (D, E) Proportion of pDCs in the spleen and LN 4 and 10 days post-sensitization to sheep globulin respectively. (F, G) Footpad swelling in mice 4 and 10 days post-sensitization to sheep globulin, respectively. Black bars represent PBS treated mice. White bars represent FL treated mice. n = 4 per group. *P<0.05, **P<0.01.
Mentions: To determine if increased populations of pDCs and Tregs induced by FL protected mice from generating effector T cell responses, PBS or FL was administered to mice for 10 days, then mice were sensitized to sheep globulin. Mice were then culled 4 or 10 days after sensitization (Fig 2A). At 4 and 10 days post-sensitization, the numbers of splenocytes and LN cells were not different between PBS and FL treated mice (Fig 2B and 2C). Four days after sensitization to sheep globulin, the proportion of CD11c+ cells remained elevated in the LN, but not the spleen of FL treated mice (spleen PBS 20.9±2.5 vs FL 19.4±2.6%, P = 0.7; LN PBS 6.6±0.3 vs FL 9.6±0.4%, P<0.005). FL treated mice had higher proportions of pDCs in spleen and LN (Fig 2D), Ten days after sensitization to sheep globulin, FL treated mice had a reduced proportion of CD11c+ cells in the LN (spleen PBS 4.3±2.2 vs FL 2.4±0.1%, P = 0.44; LN PBS 1.2±0.03 vs FL 0.9±0.02%, P<0.001), but there was no longer any detectable difference in pDC proportions (Fig 2E). No significant differences in Treg proportions were identified four days after sheep globulin sensitization between mice that had been treated with PBS or FL (spleen PBS 7.2±0.8 vs FL 8.6±0.3%, P = 0.16; LN PBS 8.6±0.1 vs FL 9.5±0.5%, P = 0.11). Four days after sheep globulin sensitisation, FL mice developed increased dermal DTH to sheep globulin, suggesting elevated pDC populations did not suppress antigen-specific immunity, but rather enhanced effector T cell function (Fig 2F). When mice were challenged with sheep globulin 10 days after sensitization, DTH was present to a similar degree in PBS and FL treated groups (Fig 2G).

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