2012-ivanov-413

On Wed, 27-Jun-2012   /   Intranasal Instillation  
Ivanov S, Fontaine J, Paget C, MachoFernandez E, Maele LV, Renneson J, Malliet I, Wolf NM, Rial A, Léger H, Ryffel B, Frisch B, Chabalgoity J, Sirard JC, Benecke A, Faveeuw C, Trottein F.
Key role for respiratory CD103+ dendritic cells, IFN-γ and IL-17 in protection against Streptococcus pneumoniae infection in response to α-galactosylceramide.
J Infect Dis. [Internet]. 2012 Jun 21 [cited 2012 Jun 27]; Available from: http://jid.oxfordjournals.org/content/early/2012/06/21/infdis.jis413
[toggle_content title=”Abstract”] Background. Exogenous activation of pulmonary invariant Natural Killer T (iNKT) cells, a population of lipid-reactive αβ T lymphocytes, by means of mucosal α-galactosylceramide (α-GalCer) administration, is a promising approach to control respiratory bacterial infections. We undertook the present study to characterize mechanisms leading to α-GalCer-mediated protection against lethal infection with S. pneumoniae serotype 1, a major respiratory pathogen in humans.
Methods and Results. α-GalCer was administered by the intranasal route before infection with S. pneumoniae. We showed that respiratory dendritic cells (DCs), most likely the CD103+ subset, play a major role in the activation (IFN-γ and IL-17 release) of pulmonary iNKT cells, whilst alveolar and interstitial macrophages are minor players. After challenge, S. pneumoniae was rapidly (4h) eliminated in the alveolar spaces, a phenomenon that depended on respiratory DCs and neutrophils, but not macrophages, and on the early production of both IFN-γ and IL-17. Protection was also associated with the synthesis of various interferon-dependent and IL-17-associated genes as revealed by transcriptomic analysis.
Conclusions. These data imply a new function for pulmonary CD103+ DCs in mucosal activation of iNKT cells and establish a critical role for both IFN-γ and IL-17 signalling pathways in mediating the innate immune response to S. pneumoniae.[/toggle_content] [toggle_content title=”Clodronate Liposome Parameters”] [custom_table]
Clodronate Concentration Total Lipid Concentration Lipid Composition Lipid Mole % Liposome Type Control Liposomes
10 mg/ml 1 46 mg/ml EPC/Chol 86/14 MLV none

1 Clodronate and lipid concentrations assumed based on information in paper (dosed 2 mg in 0.2 ml).

[/custom_table] [/toggle_content] [toggle_content title=”Animals and Dosing”] [custom_table]
Animal Description Clodronate Dose Dosing Method/Site Target Phagocytes Adjunct Dosing? Adjunct Dosing Route
C57BL/6, CD11c mice2, male, 8 w 20 µg intranasal instillation alveolar MΦ no NA

2Base strains; mutants or transgenic animals also used.

[/custom_table] [/toggle_content] [toggle_content title=”Notes”]
  1. Clodronate and lipid concentrations assumed based on referenced paper, although references provide little information as to final clodronate concentrations.
  2. Reference for clodronate liposome preparation — van Rooijen N, van Nieuwmegen R. Elimination of phagocytic cells in the spleen after intravenous injection of liposome-encapsulated dichloromethylene diphosphonate. An enzyme-histochemical study. Cell Tissue Res. 1984;238(2):355–8.
[/toggle_content][toggle_content title=”Results”]
  1. ~74% of the alveolar macrophages collected by lavage were depleted 48 h post-administration of clodronate liposomes; counts at other time points were not taken.
  2. Alveolar macrophage depletion did not affect pulmonary CFU at 4 h post-infection or mortality rate.
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