Infliximab induces downregulation of the IL-12/IL-23 axis in 6-sulfo-LacNac (slan)+ dendritic cells and macrophages

• Published in: Journal of allergy and clinical immunology Vol. 132; no. 5; pp. 1184 - 1193.e8
• Main Authors: Brunner, Patrick M., Koszik, Frieder, Reininger, Bärbel, Kalb, Madeleine L., Bauer, Wolfgang, Stingl, Georg
• Format: Journal Article
• Language: English
• Published: New York, NY Mosby, Inc 01.11.2013; Elsevier; Elsevier Limited
• Subjects: 6-sulfo-LacNac; Adult; Allergy and Immunology; Amino Sugars - metabolism; antagonists; antibodies; Antibodies, Monoclonal - pharmacology; Antigens, CD - metabolism; Apoptosis; Biological and medical sciences; Case-Control Studies; chemokine CCL20; Cloning; dendritic cells; Dendritic Cells - drug effects; Dendritic Cells - immunology; Dendritic Cells - metabolism; Dermatology; Disease; fluorescent antibody technique; Fundamental and applied biological sciences. Psychology; Fundamental immunology; Gene Expression; Humans; IL-12p40; immune response; Immune system; Immunopathology; Immunophenotyping; inflammation; Inflammation Mediators - metabolism; Infliximab; interleukin-12; Interleukin-12 - metabolism; interleukin-1beta; interleukin-23; Interleukin-23 - metabolism; intravenous injection; keratinocytes; Leukocyte Count; Leukocytes, Mononuclear - immunology; Leukocytes, Mononuclear - metabolism; macrophages; Macrophages - drug effects; Macrophages - immunology; Macrophages - metabolism; Medical sciences; messenger RNA; Metabolic disorders; Middle Aged; monocytes; Monocytes - immunology; Monocytes - metabolism; myeloid dendritic cells; patients; Proteins; Psoriasis; Psoriasis - immunology; Psoriasis - metabolism; Psoriasis. Parapsoriasis. Lichen; reverse transcriptase polymerase chain reaction; RNA, Messenger - genetics; RNA, Messenger - metabolism; Sarcoidosis. Granulomatous diseases of unproved etiology. Connective tissue diseases. Elastic tissue diseases. Vasculitis; Skin; T-lymphocytes; TNF-α; tumor necrosis factor-alpha; Tumor Necrosis Factor-alpha - biosynthesis; Tumor Necrosis Factor-alpha - genetics; 6-sulfo-LacNac; tmTNF-α; TNFR; PASI; Psoriasis; IL-12p40; PMA; MACS; myeloid dendritic cells; mDC; slan; TUNEL; TNF-α; iNOS; sTNF-α; NK; BDCA; DC; Terminal deoxynucleotidyl transferase dUTP nick end labeling; Psoriasis Area and Severity Index; Magnetic cell sorting; Inducible nitric oxide synthase; Myeloid dendritic cell; Transmembrane TNF-α (26 kDa); Dendritic cell; Blood dendritic cell antigen; Soluble TNF-α (17 kDa); Natural killer; TNF receptor; Phorbol 12-myristate 13-acetate; Immunopathology; Skin disease; Cytokine; Interleukin 12; Interleukin 23; Monoclonal antibody; Anti-Tumor Necrosis Factor-alpha; Interleukin 6; Immunology; Infliximab; Antigen presenting cell; Anticytokine; Tumor necrosis factor α; Macrophage; 6-Sulfo-LacNac
• ISSN: 0091-6749; 1097-6825; 1097-6825
• DOI: 10.1016/j.jaci.2013.05.036

The spectrum of TNF-α–producing cells in patients with psoriasis, as well as their fate during treatment with TNF-α antagonists, is not clearly defined. We sought to analyze the effects of anti–TNF-α treatment on TNF-α+ cells in the skin and blood of patients with psoriasis. Lesional psoriatic skin was analyzed by means of immunohistologic staining and quantitative RT-PCR, and peripheral blood cells were phenotypically characterized by means of multicolor immunofluorescence labeling. By using a tyramide-based signal amplification system, TNF-α was detected in dermal CD45+HLA-DR+ leukocytes consisting of CD11c+ dendritic cells and CD163+ macrophages. In peripheral blood we observed an increase in the TNF-α–producing myeloid subsets of CD14− 6-sulfo-LacNac+ dendritic cells and CD14+CD16+ “intermediate” monocytes compared with healthy control subjects. Strikingly, we did not find detectable levels of TNF-α in other cells, including keratinocytes or T cells, making these cell types unlikely targets of TNF-α blockers. Up to 48 hours after the intravenous administration of the TNF-α antagonist infliximab, we encountered no overt changes in numbers of TNF-α+ cells or signs of apoptosis in lesional psoriatic skin. Yet we observed a rapid decrease in IL-12p40, IL-1β, CCL20, and IL12RB1 mRNA levels. Consistently, TNF-α blockade during in vitro stimulation of 6-sulfo-LacNac DCs resulted in decreased production of IL-12 and IL-23 but not IL-6. In a mixed leukocyte reaction infliximab led to significantly decreased proliferation rates of T cells independent of the Fc antibody fragment. The decrease in tissue inflammation during anti–TNF-α therapy is not due to immediate killing of TNF-α–producing cells but rather results from a rapid downregulation of the pathogenic IL-12/IL-23–driven immune response.