Activation of cytotoxic lymphocytes by interferon-alpha: role of oxygen radical-producing mononuclear phagocytes

• 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.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper -- Cell- och molekylärbiologi (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Cell and Molecular Biology (hsv//eng)

Nyckelord

Antigens

CD/immunology

Antigens

CD3/immunology

Antigens

Differentiation

T-Lymphocyte/immunology

Apoptosis/drug effects/immunology

Cell Communication/physiology

Cells

Cultured

Cytotoxicity

Immunologic/drug effects/immunology

Enzyme Inhibitors/pharmacology/therapeutic use

Free Radical Scavengers/pharmacology/therapeutic use

Humans

Immune Tolerance/drug effects/ immunology

Interferon-alpha/ pharmacology

Killer Cells

Natural/drug effects/immunology

Leukocytes

Mononuclear/immunology/metabolism/secretion

Lymphocyte Activation/drug effects/ immunology

Lymphocytes/drug effects/ immunology

NADPH Oxidase/antagonists & inhibitors/metabolism

Oxidative Stress/drug effects/immunology

Phagocytes/ immunology/metabolism/secretion

Reactive Oxygen Species/ immunology/metabolism

T-Lymphocytes

Cytotoxic/drug effects/immunology

Publikations- och innehållstyp

ref (ämneskategori)

art (ämneskategori)