FMS-like tyrosine kinase 3 ligand treatment does not ameliorate experimental rapidly progressive glomerulonephritis

PLoS One. 2015 Apr 7;10(4):e0123118. doi: 10.1371/journal.pone.0123118. eCollection 2015.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Dendritic Cells / immunology*
  • Flow Cytometry
  • Globulins / immunology
  • Glomerulonephritis / immunology*
  • Glomerulonephritis / metabolism
  • Glomerulonephritis / pathology
  • Hypersensitivity, Delayed / immunology*
  • Immunity, Cellular / immunology
  • Interferon-gamma / immunology
  • Interleukin-17 / immunology
  • Kidney Glomerulus / immunology*
  • Kidney Glomerulus / metabolism
  • Kidney Glomerulus / pathology
  • Male
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Sheep
  • T-Lymphocytes, Regulatory / immunology*
  • Th1 Cells / immunology
  • fms-Like Tyrosine Kinase 3 / immunology

Substances

  • Globulins
  • Interleukin-17
  • Membrane Proteins
  • flt3 ligand protein
  • Interferon-gamma
  • fms-Like Tyrosine Kinase 3

Grants and funding

JRG and ARK have been supported by the National Health and Medical Research Council Grant Numbers 1017559 and 1048575 respectively (https://www.nhmrc.gov.au). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.