Clemastine causes immune suppression through inhibition of extracellular signal- regulated kinase–dependent proinflammatory cytokines Pål Johansen, PhD,

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Clemastine causes immune suppression through inhibition of extracellular signal- regulated kinase–dependent proinflammatory cytokines Pål Johansen, PhD, Andreas Weiss, PhD, Antonia Bünter, MSc, Ying Waeckerle-Men, PhD, Antonia Fettelschoss, MSc, Bernhard Odermatt, MD, Thomas M. Kündig, MD Journal of Allergy and Clinical Immunology Volume 128, Issue 6, Pages 1286-1294 (December 2011) DOI: 10.1016/j.jaci.2011.06.023 Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 Fatal growth of LM in antihistamine-treated mice. A, Survival of C57BL/6 mice infected with 1 × 104 CFUs of LM and treated daily (n = 7) or not (Untr, n = 4) with 100 μg of clemastine (Clem) starting 1 day preinfection. B, Bacterial counts in spleens harvested 3 days postinfection with 1 × 105 CFUs of LM. Data are representative of 3 experiments (n = 4). C, Bacterial growth in spleen of mice (n = 4) treated daily with 100 μg of Clem, azathioprine (Aza), or dexamethasone (Dex) starting 1 day preinfection (1 × 104 CFUs). The experiment was repeated once (n = 4). D-F, Infected mice were treated daily with 100 μg of Clem, desloratadine (Des), cetirizine (Cet), or dimetindene (Dim). Changes in body weight were monitored (Fig 1, D), and bacterial growth was determined (n = 6) (Fig 1, E). Histologic analysis of spleens from infected mice. The arrowheads indicate LM (Fig 1, F). Journal of Allergy and Clinical Immunology 2011 128, 1286-1294DOI: (10.1016/j.jaci.2011.06.023) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 Immunosuppression by clemastine (Clem) is TNF-α and IL-6 dependent. A, Cytokine secretion from peritoneal macrophages cultured in triplicates with or without Clem before being infected with LM. The experiment was repeated once. B, Cytokine secretion from macrophages cultured in triplicates with Clem or histamine (Hist) and with LPS. The experiment was repeated twice. The P values were calculated without Dunn’s corrections. C, Real-time PCR analysis of cytokine and chemokine expression in macrophages MACS isolated from mice treated with Clem and infected. The experiment was repeated once for analysis of secreted cytokines and chemokines on a protein array. D, Mice were pretreated or not (Untr) with Clem before infection. Four hours postinfection, blood (left panel) and peritoneal cells (right panel) were harvested and analyzed for secretion of cytokines (n = 5). E-G, TNF-α–deficient mice were treated or not treated daily with Clem and infected with 5 × 104 CFUs of LM. Body-weight loss (Fig 2, E), bacterial growth in livers and spleens (Fig 2, F), and liver histology (Fig 2, G) were analyzed 3 days postinfection. Journal of Allergy and Clinical Immunology 2011 128, 1286-1294DOI: (10.1016/j.jaci.2011.06.023) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 Clemastine suppresses antibacterial immunity independent of H1R expression. A-C, H1R-deficient mice were infected with LM and treated or not (Untr) with clemastine (Clem) (n = 4-5). Listeriosis was measured by monitoring (Fig 3, A) body weight, (Fig 3, B) bacterial growth, and (Fig 3, C) histology in spleens and livers. The histochemical analysis shows sections stained for LM. Equivalent experiments were performed thrice. D, TNF-α secretion from peritoneal macrophages isolated from wild-type or H1R-deficient mice and stimulated with LPS in the presence or absence of Clem. The experiment was performed twice. Journal of Allergy and Clinical Immunology 2011 128, 1286-1294DOI: (10.1016/j.jaci.2011.06.023) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 Clemastine (Clem) suppresses septic shock in mice. Survival of BALB/c mice (n = 8) after LPS-induced sepsis. Mice received immunotherapy with Clem or dexamethasone (Dex) or did not receive immunotherapy (Untr). The P value describes the significance of Untr versus Clem-treated mice as calculated by using the Gehan-Breslow-Wilcoxon test (P = .015). The experiment was repeated twice. Journal of Allergy and Clinical Immunology 2011 128, 1286-1294DOI: (10.1016/j.jaci.2011.06.023) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 5 Clemastine hampers both TNF-α and IL-6 secretion from and ERK signaling in human monocytes. A and B, Human monocytes were isolated from PBMCs and precultured in quadruples with or without clemastine (Clem) and then stimulated with LPS. The supernatants (n = 4) were analyzed for (Fig 5, A) TNF-α and (Fig 5, B) IL-6. P values were calculated by using Kruskal-Wallis H tests without Dunn’s corrections. C and D, Healthy volunteers were infused with 2 mg of Clem (n = 5) or placebo (Untr, n = 5) in a clinical trial. Cells from venous blood were collected before and after the treatment, stimulated with LPS, and analyzed for (Fig 5, C) TNF-α and (Fig 5, D) IL-6. E, Monocytes isolated from human PBMCs were stimulated as described above. The cell lysates were analyzed by using immunoblot as indicated. The experiment was repeated twice. Journal of Allergy and Clinical Immunology 2011 128, 1286-1294DOI: (10.1016/j.jaci.2011.06.023) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 6 Clemastine (Clem) suppresses antibacterial immunity independent of the Toll-like receptor–associated anchor protein MyD88. MyD88-deficient mice were infected with 1 × 105 CFUs of LM and treated or not treated (Untr) daily with 100 μg of Clem (n = 5). The development of listeriosis was measured by monitoring (A) body weight and (B) bacterial growth in spleens (left panel) and livers (right panel) 3 days postinfection. Journal of Allergy and Clinical Immunology 2011 128, 1286-1294DOI: (10.1016/j.jaci.2011.06.023) Copyright © 2011 American Academy of Allergy, Asthma & Immunology Terms and Conditions