title: Activation of cytotoxic lymphocytes by interferon-alpha: role of oxygen radical-producing mononuclear phagocytes.
abstract: A significant part of the therapeutic benefit of interferon-alpha (IFN-alpha) therapy in malignant diseases and in chronic viral infections is assumed to result from activation of lymphocytes with natural killer (NK) and T cell phenotype. In tumor tissue and in chronically infected tissue, the function and viability of these lymphocytes are frequently impaired. Mononuclear phagocyte (MP)-derived reactive oxygen species (ROS) have been proposed to contribute to the lymphocyte suppression in these tissues. Here, we report that three types of human cytotoxic lymphocytes of relevance to immunoactivation by IFN-alpha, CD3epsilon+/8+/56- T cells, CD3epsilon-/56+ NK cells, and CD3epsilon+/56+ NK/T cells became anergic to IFN-alpha induction of the cell-surface activation marker CD69 after exposure to autologous MPs in vitro. In addition to their incapacity to express CD69, cytotoxic lymphocytes acquired features characteristic of apoptosis after incubation with MPs. The lymphocyte apoptosis and nonresponsiveness to IFN-alpha were prevented by two inhibitors of reduced nicotinamide adenine dinucleotide phosphate oxidase-dependent formation of ROS in MPs, histamine dihydrochloride and diphenylene ionodonium, as well as by catalase, a scavenger of ROS. We conclude that MP-derived ROS may negatively affect IFN-alpha-induced immunostimulation and propose that ROS inhibitors or scavengers may be useful to improve lymphocyte activation during treatment with IFN-alpha.
authors.affiliation: Department of Hematology, University of Lund, Sweden.
authors.forename: Markus
authors.initials: M
authors.lastname: Hansson
authors.forename: Ana
authors.initials: A
authors.lastname: Romero
authors.forename: Fredrik
authors.initials: F
authors.lastname: Thorén
authors.forename: Svante
authors.initials: S
authors.lastname: Hermodsson
authors.forename: Kristoffer
authors.initials: K
authors.lastname: Hellstrand
mesh_terms: D015703:Antigens, CD / Q000276:immunology; D000945:Antigens, Differentiation, T-Lymphocyte / Q000276:immunology; D017209:Apoptosis / Q000187:drug effects / Q000276:immunology; D017252:CD3 Complex / Q000276:immunology; D002450:Cell Communication / Q000502:physiology; D002478:Cells, Cultured; D003602:Cytotoxicity, Immunologic / Q000187:drug effects / Q000276:immunology; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D016166:Free Radical Scavengers / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D007108:Immune Tolerance / Q000187:drug effects / Q000276:immunology*; D016898:Interferon-alpha / Q000494:pharmacology*; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology; D037181:Lectins, C-Type; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology*; D008214:Lymphocytes / Q000187:drug effects / Q000276:immunology*; D019255:NADPH Oxidases / Q000037:antagonists & inhibitors / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects / Q000276:immunology; D010586:Phagocytes / Q000276:immunology* / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000276:immunology* / Q000378:metabolism; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects / Q000276:immunology; D000099192:CD69 Antigens
chemical_list: D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D017252:CD3 Complex; D004791:Enzyme Inhibitors; D016166:Free Radical Scavengers; D016898:Interferon-alpha; D037181:Lectins, C-Type; D019255:NADPH Oxidases; D017382:Reactive Oxygen Species; D000099192:CD69 Antigens; C485468:Cd3e protein, mouse