title: Early or late IL-10 blockade enhances Th1 and Th17 effector responses and promotes fungal clearance in mice with cryptococcal lung infection.
abstract: The potent immunoregulatory properties of IL-10 can counteract protective immune responses and, thereby, promote persistent infections, as evidenced by studies of cryptococcal lung infection in IL-10-deficient mice. To further investigate how IL-10 impairs fungal clearance, the current study used an established murine model of C57BL/6J mice infected with Cryptococcus neoformans strain 52D. Our results demonstrate that fungal persistence is associated with an early and sustained expression of IL-10 by lung leukocytes. To examine whether IL-10-mediated immune modulation occurs during the early or late phase of infection, assessments of fungal burden and immunophenotyping were performed on mice treated with anti-IL-10R-blocking Ab at 3, 6, and 9 d postinfection (dpi) (early phase) or at 15, 18, and 21 dpi (late phase). We found that both early and late IL-10 blockade significantly improved fungal clearance within the lung compared with isotype control treatment when assessed 35 dpi. Immunophenotyping identified that IL-10 blockade enhanced several critical effector mechanisms, including increased accumulation of CD4(+) T cells and B cells, but not CD8(+) T cells; specific increases in the total numbers of Th1 and Th17 cells; and increased accumulation and activation of CD11b(+) dendritic cells and exudate macrophages. Importantly, IL-10 blockade effectively abrogated dissemination of C. neoformans to the brain. Collectively, this study identifies early and late cellular and molecular mechanisms through which IL-10 impairs fungal clearance and highlights the therapeutic potential of IL-10 blockade in the treatment of fungal lung infections.
authors.affiliation: Research Service, Veterans Affairs Ann Arbor Healthcare System, Department of Veterans Affairs Health System, Ann Arbor, MI 48105; Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, MI 48109;
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Murdock
authors.affiliation: Research Service, Veterans Affairs Ann Arbor Healthcare System, Department of Veterans Affairs Health System, Ann Arbor, MI 48105; Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, MI 48109;
authors.forename: Seagal
authors.initials: S
authors.lastname: Teitz-Tennenbaum
authors.affiliation: Research Service, Veterans Affairs Ann Arbor Healthcare System, Department of Veterans Affairs Health System, Ann Arbor, MI 48105; Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, MI 48109;
authors.forename: Gwo-Hsiao
authors.initials: GH
authors.lastname: Chen
authors.affiliation: Research Service, Veterans Affairs Ann Arbor Healthcare System, Department of Veterans Affairs Health System, Ann Arbor, MI 48105; Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, MI 48109;
authors.forename: Anthony J
authors.initials: AJ
authors.lastname: Dils
authors.affiliation: Research Service, Veterans Affairs Ann Arbor Healthcare System, Department of Veterans Affairs Health System, Ann Arbor, MI 48105; Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, MI 48109;
authors.forename: Antoni N
authors.initials: AN
authors.lastname: Malachowski
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, MI 48109; Pulmonary Section, Medical Service, Veterans Affairs Ann Arbor Healthcare System, Department of Veterans Affairs Health System, Ann Arbor, MI 48105; and Graduate Program in Immunology, University of Michigan Health System, Ann Arbor, MI 48109.
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Curtis
authors.affiliation: Research Service, Veterans Affairs Ann Arbor Healthcare System, Department of Veterans Affairs Health System, Ann Arbor, MI 48105; Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, MI 48109; Graduate Program in Immunology, University of Michigan Health System, Ann Arbor, MI 48109.
authors.forename: Michal A
authors.initials: MA
authors.lastname: Olszewski
authors.affiliation: Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, MI 48109; Pulmonary Section, Medical Service, Veterans Affairs Ann Arbor Healthcare System, Department of Veterans Affairs Health System, Ann Arbor, MI 48105; and Graduate Program in Immunology, University of Michigan Health System, Ann Arbor, MI 48109 oster@umich.edu.
authors.forename: John J
authors.initials: JJ
authors.lastname: Osterholzer
mesh_terms: D000818:Animals; D019138:Antibodies, Blocking / Q000008:administration & dosage; D001402:B-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D003453:Cryptococcosis / Q000276:immunology / Q000628:therapy*; D003455:Cryptococcus neoformans; D003713:Dendritic Cells / Q000276:immunology; D016130:Immunophenotyping; D016753:Interleukin-10 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000276:immunology; D008172:Lung Diseases, Fungal / Q000276:immunology* / Q000382:microbiology; D018655:Lymphocyte Count; D008264:Macrophages / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D018417:Th1 Cells / Q000276:immunology*; D058504:Th17 Cells / Q000276:immunology*
chemical_list: D019138:Antibodies, Blocking; C556062:IL10 protein, mouse; D016753:Interleukin-10