title: Flt3 ligand treatment reverses endotoxin tolerance-related immunoparalysis.
abstract: Endotoxin tolerance, the secondary blunting of a subset of microbial product-driven responses, is presumed to provide protection from pathological hyperactivation of the innate immune system during infection. However, endotoxin tolerance can itself be harmful. A significant percentage of sepsis survivors exhibit the phenotype of systemic endotoxin tolerance, a state termed immunoparalysis. Similar immune hyporeactivity, associated with an elevated risk of succumbing to bacterial superinfection, is also seen in the aftermath of major trauma, surgery, and burns. We recently demonstrated that in vivo endotoxin tolerance in murine models involves dendritic cell loss as well as alterations in the responsiveness of macrophages and remaining dendritic cells. Furthermore, the kinetics of recovery from immunoparalysis-associated inhibition of proinflammatory and immunoregulatory cytokine production directly parallels the kinetics of dendritic cell repopulation in these models. Given this, we examined whether recovery from immunoparalysis could be accelerated therapeutically with flt3 ligand, a growth factor that stimulates the differentiation and mobilization of dendritic cells. Notably, administration of flt3 ligand rapidly reverses immunoparalysis in vivo, accelerating and amplifying repopulation of tissues with proinflammatory and immunoregulatory cytokine-producing dendritic cells.
authors.affiliation: Department of Dermatology, University of Pennsylvania, Philadelphia, 19104, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Wysocka
authors.forename: Luis J
authors.initials: LJ
authors.lastname: Montaner
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Karp
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage / Q000627:therapeutic use*; D000818:Animals; D039521:CD11c Antigen / Q000096:biosynthesis; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D005260:Female; D006801:Humans; D007108:Immune Tolerance / Q000235:genetics; D007274:Injections, Intraperitoneal; D018664:Interleukin-12 / Q000096:biosynthesis; D008024:Ligands; D008070:Lipopolysaccharides / Q000037:antagonists & inhibitors / Q000633:toxicity*; D008264:Macrophages / Q000166:cytology / Q000276:immunology; D008565:Membrane Proteins / Q000008:administration & dosage / Q000627:therapeutic use*; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D012772:Shock, Septic / Q000235:genetics / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D013154:Spleen / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
chemical_list: D000276:Adjuvants, Immunologic; D039521:CD11c Antigen; D008024:Ligands; D008070:Lipopolysaccharides; D008565:Membrane Proteins; D014409:Tumor Necrosis Factor-alpha; C084881:flt3 ligand protein; D018664:Interleukin-12