Flt3 Ligand Treatment Reverses Endotoxin Tolerance-Related Immunoparalysis

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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.