Infliximab induces downregulation of the IL-12/IL-23 axis in 6-sulfo-LacNac (slan)+ dendritic cells and macrophages Patrick M. Brunner, MD, Frieder Koszik,

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Infliximab induces downregulation of the IL-12/IL-23 axis in 6-sulfo-LacNac (slan)+ dendritic cells and macrophages Patrick M. Brunner, MD, Frieder Koszik, PhD, Bärbel Reininger, Madeleine L. Kalb, MD, Wolfgang Bauer, MD, Georg Stingl, MD Journal of Allergy and Clinical Immunology Volume 132, Issue 5, Pages 1184-1193.e8 (November 2013) DOI: 10.1016/j.jaci.2013.05.036 Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 Characterization of tmTNF-α+ skin cells in healthy subjects and patients with psoriasis. A-D, Conventional immunohistochemistry for tmTNF-α was done on sections of healthy (Fig 1, A) and lesional psoriatic skin (Fig 1, B and C), including an isotype control (Fig 1, D). E-J and L-N, Tyramide signal amplification–based immunofluorescence was used to visualize tmTNF-α in lesional (Fig 1, E-J and L) and nonlesional (Fig 1, M and N) psoriatic skin counterstained for lineage markers of individual cell types. K, Flow cytometric analysis for CD11c, CD163, and HLA-DR surface expression of living (ie, 7-amino-actinomycin D−) bulk dermal CD3− leukocytes from lesional psoriatic skin. Pictures are representative of at least 6 individual patients. Journal of Allergy and Clinical Immunology 2013 132, 1184-1193.e8DOI: (10.1016/j.jaci.2013.05.036) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 Characterization of tmTNF-α+ skin cells in healthy subjects and patients with psoriasis. A-D, Conventional immunohistochemistry for tmTNF-α was done on sections of healthy (Fig 1, A) and lesional psoriatic skin (Fig 1, B and C), including an isotype control (Fig 1, D). E-J and L-N, Tyramide signal amplification–based immunofluorescence was used to visualize tmTNF-α in lesional (Fig 1, E-J and L) and nonlesional (Fig 1, M and N) psoriatic skin counterstained for lineage markers of individual cell types. K, Flow cytometric analysis for CD11c, CD163, and HLA-DR surface expression of living (ie, 7-amino-actinomycin D−) bulk dermal CD3− leukocytes from lesional psoriatic skin. Pictures are representative of at least 6 individual patients. Journal of Allergy and Clinical Immunology 2013 132, 1184-1193.e8DOI: (10.1016/j.jaci.2013.05.036) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 A and B, mDCs characterized by lineage negativity (ie, CD3−, CD14−, CD19−, and CD56−) and expression of HLA-DR and CD11c (Fig 2, A) were analyzed for the subset-specific surface markers BDCA-1, CD16, BDCA-3, and slan (Fig 2, B). Relative distribution of these mDC subsets of healthy control subjects (HC), untreated patients with psoriasis (PSO), and adalimumab-treated patients with a PASI score of less than 1 (PSO treated). Dot plots depicted are representative of at least 8 individual experiments. *P < .05, **P < .01, and ***P < .001, 2-tailed Student t test with the Bonferroni-Holm correction. Journal of Allergy and Clinical Immunology 2013 132, 1184-1193.e8DOI: (10.1016/j.jaci.2013.05.036) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 A-C, Distribution of monocyte subsets in PBMCs from healthy control subjects and patients with psoriasis. Gating strategy (Fig 3, A) for classical (CD14+CD16−), intermediate (CD14+CD16+), and nonclassical (CD14dimCD16+), as well as CD14dimslan+ monocyte subsets with representative dot plots for patients with psoriasis (Fig 3, B) and healthy control subjects (Fig 3, C). D and E, Percentage of monocyte subsets in healthy control subjects (HC), untreated patients with psoriasis (PSO), and adalimumab-treated patients with a PASI score of less than 1 (PSO treated). *P < .05, 2-tailed Student t test with the Bonferroni-Holm correction. Journal of Allergy and Clinical Immunology 2013 132, 1184-1193.e8DOI: (10.1016/j.jaci.2013.05.036) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 In vitro production of TNF-α in PBMCs from patients with psoriasis. A-F, mDCs (Fig 4, A) and monocytes (Fig 4, B), plasmacytoid DCs (Fig 4, C), B cells (Fig 4, D), NK cells (Fig 4, E), and T cells (Fig 4, F) were analyzed, and representative dot plots are shown. G, T cells produced TNF-α only after stimulation with PMA/ionomycin. H, Fold change of TNF-α+ mDCs in patients with psoriasis compared with healthy control subjects depending on disease severity (healthy control population [n = 15] normalized to 1). PASI score less than 10 = mild-to-moderate disease activity (n = 5); PASI score greater than 10 = moderate-to-severe disease activity (n = 10). Whiskers, 5th-95th percentiles. *P < .05, 2-tailed Student t test. I-K, These mDC subsets (alternative gating strategy depicted in Fig 4, I) were further characterized for the subset-specific surface markers BDCA-1, CD16, BDCA-3, and slan (Fig 4, J and K). Dot plots shown are representative for at least 8 individual experiments. Journal of Allergy and Clinical Immunology 2013 132, 1184-1193.e8DOI: (10.1016/j.jaci.2013.05.036) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 5 A-E, Before (pre) and 16 or 48 hours after (post) a single intravenous infusion of infliximab (5 mg/kg body weight), we quantified apoptotic cells with a TUNEL assay (Fig 5, A), TNF-α+ cells through tyramide signal amplification–based immunofluorescence (white line denotes dermoepidermal junction, and dotted line indicates skin surface; Fig 5, B), and CD11c+ DCs, CD163+ macrophages, and CD3+ T cells by using conventional immunohistochemistry (Fig 5, C-E). F, Changes in mRNA levels at 16 (n = 7) and 48 (n = 6) hours were evaluated by using quantitative RT-PCR. G, Levels in supernatants of IL-12, IL-23, and IL-6 (intact cytokines) produced by LPS-stimulated slanDCs isolated from buffy coat preparations with or without TNF-α blockade by using infliximab. H, Tritiated thymidine uptake by T cells in an allogeneic mixed leukocyte reaction of irradiated slanDCs isolated from buffy coat preparations measured on day 6 of culture. I, Anti-CD3/anti-CD28–driven T-cell proliferation measured on day 4 of culture. Rituximab served as a control antibody. *P < .05, **P < .01, and ***P < .001, paired (Fig 5, F) and unpaired (Fig 5, G) Student t test with the Bonferroni-Holm correction. Journal of Allergy and Clinical Immunology 2013 132, 1184-1193.e8DOI: (10.1016/j.jaci.2013.05.036) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E1 A, Coexpression of CD16 and slan on DCs from peripheral blood without prior incubation/stimulation (representative dot plots for gating strategy) and frequencies of CD16+ and slan+ DCs in PBMCs from our entire study population (ie, healthy control subjects and patients with psoriasis, with 1 dot representing each subject tested). B, Tyramide signal amplification–based immunofluorescence staining of tmTNF-α in lesional psoriatic skin counterstained with slan (clone DD2). The picture is representative of at least 3 independent experiments. C, Expression levels (histograms) of homing receptors on DCs spontaneously producing TNF-α in vitro compared with their TNF-α− counterparts, both from patients with psoriasis. Histograms are representative for 5 individual experiments. D, MACS-isolated slan+ mDCs, as well as BDCA-1+ mDCs from buffy coat preparations of healthy control subjects, were stimulated with LPS or peptidoglycan for 12 hours, and the TNF-α level was measured in the cell-culture supernatant. The figure shown is representative of 5 independent experiments. n.d., Not detected. Journal of Allergy and Clinical Immunology 2013 132, 1184-1193.e8DOI: (10.1016/j.jaci.2013.05.036) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E2 A and B, Purity of CD16+ monocytes isolated from PBMCs of patients with psoriasis and healthy control subjects (Fig E2, A) and their CD16 expression levels after 24 hours of culture with (gray line) or without (black line) 100 ng/mL LPS (Fig E2, B). Dot plots and histograms are representative of at least 3 independent experiments. Journal of Allergy and Clinical Immunology 2013 132, 1184-1193.e8DOI: (10.1016/j.jaci.2013.05.036) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E3 A-C, Biotinylated anti–TNF-α antibodies (infliximab, adalimumab, and sc52250) and etanercept were either incubated with keratinocytes preincubated with sTNF-α (Fig E3, A and B) or with the murine cell line BW5147 overexpressing tmTNF-α (Fig E3, C). Histograms shown are representative of at least 3 independent experiments. Journal of Allergy and Clinical Immunology 2013 132, 1184-1193.e8DOI: (10.1016/j.jaci.2013.05.036) Copyright © 2013 American Academy of Allergy, Asthma & Immunology Terms and Conditions