title: Endotoxin-induced myeloid-derived suppressor cells inhibit alloimmune responses via heme oxygenase-1.
abstract: Inflammation and cancer are associated with impairment of T-cell responses by a heterogeneous population of myeloid-derived suppressor cells (MDSCs) coexpressing CD11b and GR-1 antigens. MDSCs have been recently implicated in costimulation blockade-induced transplantation tolerance in rats, which was under the control of inducible NO synthase (iNOS). Herein, we describe CD11b+GR-1+MDSC-compatible cells appearing after repetitive injections of lipopolysaccharide (LPS) using a unique mechanism of suppression. These cells suppressed T-cell proliferation and Th1 and Th2 cytokine production in both mixed lymphocyte reaction and polyclonal stimulation assays. Transfer of CD11b+ cells from LPS-treated mice in untreated recipients significantly prolonged skin allograft survival. They produced large amounts of IL-10 and expressed heme oxygenase-1 (HO-1), a stress-responsive enzyme endowed with immunoregulatory and cytoprotective properties not previously associated with MDSC activity. HO-1 inhibition by the specific inhibitor, SnPP, completely abolished T-cell suppression and IL-10 production. In contrast, neither iNOS nor arginase 1 inhibition did affect suppression. Importantly, HO-1 inhibition before CD11b+ cell transfer prevented the delay of allograft rejection revealing a new MDSC-associated suppressor mechanism relevant for transplantation.
authors.affiliation: Institute for Medical Immunology, Université Libre de Bruxelles, Gosselies, Belgium.
authors.forename: V
authors.initials: V
authors.lastname: De Wilde
authors.forename: N
authors.initials: N
authors.lastname: Van Rompaey
authors.forename: M
authors.initials: M
authors.lastname: Hill
authors.forename: J F
authors.initials: JF
authors.lastname: Lebrun
authors.forename: P
authors.initials: P
authors.lastname: Lemaître
authors.forename: F
authors.initials: F
authors.lastname: Lhommé
authors.forename: C
authors.initials: C
authors.lastname: Kubjak
authors.forename: B
authors.initials: B
authors.lastname: Vokaer
authors.forename: G
authors.initials: G
authors.lastname: Oldenhove
authors.forename: L M
authors.initials: LM
authors.lastname: Charbonnier
authors.forename: M C
authors.initials: MC
authors.lastname: Cuturi
authors.forename: M
authors.initials: M
authors.lastname: Goldman
authors.forename: A
authors.initials: A
authors.lastname: Le Moine
mesh_terms: D000818:Animals; D039481:CD11b Antigen / Q000096:biosynthesis; D049109:Cell Proliferation; D004731:Endotoxins / Q000378:metabolism*; D051547:Heme Oxygenase-1 / Q000378:metabolism*; D007107:Immune System; D016753:Interleukin-10 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D022423:Myeloid Cells / Q000166:cytology*; D019707:Receptors, Chemokine / Q000096:biosynthesis / Q000276:immunology; D013601:T-Lymphocytes / Q000166:cytology; D018417:Th1 Cells / Q000166:cytology; D018418:Th2 Cells / Q000166:cytology
chemical_list: D039481:CD11b Antigen; D004731:Endotoxins; C503133:Gr-1 protein, mouse; D008070:Lipopolysaccharides; D019707:Receptors, Chemokine; D016753:Interleukin-10; D051547:Heme Oxygenase-1