title: IL-7 promotes T cell viability, trafficking, and functionality and improves survival in sepsis.
abstract: Sepsis is a highly lethal disorder characterized by widespread apoptosis-induced depletion of immune cells and the development of a profound immunosuppressive state. IL-7 is a potent antiapoptotic cytokine that enhances immune effector cell function and is essential for lymphocyte survival. In this study, recombinant human IL-7 (rhIL-7) efficacy and potential mechanisms of action were tested in a murine peritonitis model. Studies at two independent laboratories showed that rhIL-7 markedly improved host survival, blocked apoptosis of CD4 and CD8 T cells, restored IFN-gamma production, and improved immune effector cell recruitment to the infected site. Importantly, rhIL-7 also prevented a hallmark of sepsis (i.e., the loss of delayed-type hypersensitivity), which is an IFN-gamma- and T cell-dependent response. Mechanistically, rhIL-7 significantly increased the expression of the leukocyte adhesion markers LFA-1 and VLA-4, consistent with its ability to improve leukocyte function and trafficking to the infectious focus. rhIL-7 also increased the expression of CD8. The potent antiapoptotic effect of rhIL-7 was due to increased Bcl-2, as well as to a dramatic decrease in sepsis-induced PUMA, a heretofore unreported effect of IL-7. If additional animal studies support its efficacy in sepsis and if current clinical trials continue to confirm its safety in diverse settings, rhIL-7 should be strongly considered for clinical trials in sepsis.
authors.affiliation: Department of Anesthesiology, Washington University School of Medicine, St Louis, MO 63110, USA.
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Unsinger
authors.forename: Margaret
authors.initials: M
authors.lastname: McGlynn
authors.forename: Kevin R
authors.initials: KR
authors.lastname: Kasten
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Hoekzema
authors.forename: Eizo
authors.initials: E
authors.lastname: Watanabe
authors.forename: Jared T
authors.initials: JT
authors.lastname: Muenzer
authors.forename: Jacquelyn S
authors.initials: JS
authors.lastname: McDonough
authors.forename: Johannes
authors.initials: J
authors.lastname: Tschoep
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Ferguson
authors.forename: Jonathan E
authors.initials: JE
authors.lastname: McDunn
authors.forename: Michel
authors.initials: M
authors.lastname: Morre
authors.forename: David A
authors.initials: DA
authors.lastname: Hildeman
authors.forename: Charles C
authors.initials: CC
authors.lastname: Caldwell
authors.forename: Richard S
authors.initials: RS
authors.lastname: Hotchkiss
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002470:Cell Survival; D002634:Chemotaxis, Leukocyte / Q000187:drug effects / Q000276:immunology*; D006801:Humans; D006968:Hypersensitivity, Delayed / Q000276:immunology; D020381:Interleukin-17 / Q000276:immunology* / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D011994:Recombinant Proteins / Q000276:immunology / Q000494:pharmacology; D020133:Reverse Transcriptase Polymerase Chain Reaction; D018805:Sepsis / Q000188:drug therapy / Q000276:immunology*; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*
chemical_list: D020381:Interleukin-17; D011994:Recombinant Proteins