title: Research in practice: the impact of interferon-α therapy on immune tolerance.
abstract: Interferon-α (IFN-α) is the only drug approved for adjuvant therapy of malignant melanoma and is also used in the treatment of hematological and solid tumors. Along with its proven clinical efficacy, IFN-α produces several side effects, particularly with regard to autoimmune disorders. Curious about symptoms of autoimmunity during IFN-α therapy, we asked whether IFN-α directly impacts on immune tolerance. We found that IFN-α does alter the function of tolerogenic dendritic cells (DC) as well as of induced and naturally occurring T-regulatory cells (nTregs). IFN-α blocks the tolerogenic phenotype of DC by inducing maturation and thus preventing the induction of inducible Tregs by DC. It also has direct effects on nTregs. IFN-α reduces cAMP in Tregs via ERK/phosphodiesterase-mediated pathways. Since cAMP is essentially involved in suppression by nTregs, the IFN-α-dependent reduction of cAMP levels abolishes the suppressive capacity of nTregs. Therefore, Tregs are incapable of suppressing the activity of effector T cells and natural killer cells, resulting in tumor rejection. Thus, IFN-α overcomes immunological tolerance processes, leading to an improved immunostimulation and efficient tumor rejection, but also increases the risk of autoimmunity.
authors.affiliation: Department of Dermatology, Johannes Gutenberg-Universität Mainz.
authors.forename: Verena
authors.initials: V
authors.lastname: Raker
authors.forename: Kerstin
authors.initials: K
authors.lastname: Steinbrink
mesh_terms: D000818:Animals; D001327:Autoimmune Diseases / Q000139:chemically induced* / Q000276:immunology* / Q000473:pathology; D006801:Humans; D007108:Immune Tolerance / Q000187:drug effects* / Q000276:immunology; D007155:Immunologic Factors / Q000009:adverse effects / Q000627:therapeutic use; D016898:Interferon-alpha / Q000009:adverse effects / Q000276:immunology / Q000494:pharmacology*; D018448:Models, Immunological; D009369:Neoplasms / Q000188:drug therapy / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology*
chemical_list: D007155:Immunologic Factors; D016898:Interferon-alpha