Synergistic antipruritic effects of gamma aminobutyric acid A and B agonists in a mouse model of atopic dermatitis Ferda Cevikbas, PhD, Joao M. Braz,

Slides:

Advertisements

Similar presentations

“Inflammatory skin march”: IL-1–mediated skin inflammation, atopic dermatitis, and psoriasis to cardiovascular events Keiichi Yamanaka, MD, PhD, Hitoshi.

Advertisements

Repeated low-dose intradermal allergen injection suppresses allergen-induced cutaneous late responses Giuseppina Rotiroti, MD, Mohamed Shamji, PhD, Stephen.

Cyclosporine in patients with atopic dermatitis modulates activated inflammatory pathways and reverses epidermal pathology Saakshi Khattri, MD, Avner.

Dorothea Dijkstra, MSc, Rob Leurs, PhD, Paul Chazot, PhD, Fiona C

Allergen-induced expression of IL-25 and IL-25 receptor in atopic asthmatic airways and late-phase cutaneous responses Chris J. Corrigan, MD, PhD, Wei.

Histamine H4 receptor antagonists are superior to traditional antihistamines in the attenuation of experimental pruritus Paul J. Dunford, MSc, Kacy N.

Liping Xie, MD, John T. Schroeder, PhD, Jacqueline M

A sensory neuron–expressed IL-31 receptor mediates T helper cell–dependent itch: Involvement of TRPV1 and TRPA1 Ferda Cevikbas, PhD, Xidao Wang, PhD,

Intrinsic atopic dermatitis shows similar TH2 and higher TH17 immune activation compared with extrinsic atopic dermatitis Mayte Suárez-Fariñas, PhD,

Alefacept (lymphocyte function-associated molecule 3/IgG fusion protein) treatment for atopic eczema Dagmar Simon, MD, Jennifer Wittwer, MD, Ganna Kostylina,

Histamine H2 receptor stimulation upregulates TH2 chemokine CCL17 production in human M2a macrophages Susanne Mommert, PhD, Karl Gregor, MD, Kristine.

Inflammatory marker analysis in psoriatic skin under topical phosphodiesterase 4 inhibitor treatment Lennart M. Roesner, PhD, Petra Kienlin, Gabriele.

Therapeutic pipeline for atopic dermatitis: End of the drought?

Is 9 more than 2 also in allergic airway inflammation?

Involvement of TRPV4 in Serotonin-Evoked Scratching

Color-coded real-time cellular imaging of lung T-lymphocyte accumulation and focus formation in a mouse asthma model Akihiro Hasegawa, PhD, Katsuhiro.

Signaling through FcRγ-associated receptors on dendritic cells drives IL-33–dependent TH2-type responses Melissa Y. Tjota, BA, Cara L. Hrusch, PhD, Kelly.

Peripheral serotonin receptor 2B and transient receptor potential channel 4 mediate pruritus to serotonergic antidepressants in mice Sang Hoon Lee, PhD,

Allergic skin diseases

Reversal of atopic dermatitis with narrow-band UVB phototherapy and biomarkers for therapeutic response Suzanne Tintle, BS, Avner Shemer, MD, Mayte Suárez-Fariñas,

An Infant with Atopic Dermatitis and Itching After Ingestion of Milk

Effects of lidocaine on regulatory T cells in atopic dermatitis

Chang Xiao, MD, PhD, Jocelyn M

Allergen-induced expression of IL-25 and IL-25 receptor in atopic asthmatic airways and late-phase cutaneous responses Chris J. Corrigan, MD, PhD, Wei.

IL-22–producing “T22” T cells account for upregulated IL-22 in atopic dermatitis despite reduced IL-17–producing TH17 T cells Kristine E. Nograles, MD,

Differential roles for the IL-9/IL-9 receptor α-chain pathway in systemic and oral antigen–induced anaphylaxis Heather Osterfeld, BSc, Richard Ahrens,

Cheng-Chiu Huang, PhD, Yu Shin Kim, PhD, William P

Lieuwe D. Bos, MSc, PhD, Peter J. Sterk, MD, PhD, Stephen J

Toll-like receptor 3 enhances late-phase reaction of experimental allergic conjunctivitis Mayumi Ueta, MD, PhD, Satoshi Uematsu, MD, PhD, Shizuo Akira,

Exposure to food allergens through inflamed skin promotes intestinal food allergy through the thymic stromal lymphopoietin–basophil axis Mario Noti,

The potential pharmacologic mechanisms of omalizumab in patients with chronic spontaneous urticaria Tse Wen Chang, PhD, Christina Chen, BS, Chien-Jen.

A network-based analysis of the late-phase reaction of the skin

The Janus kinase inhibitor JTE-052 improves skin barrier function through suppressing signal transducer and activator of transcription 3 signaling Wataru.

Mast cell–derived prostaglandin D2 attenuates anaphylactic reactions in mice Tatsuro Nakamura, DVM, PhD, Yuki Fujiwara, BSc, Ryota Yamada, BSc, Wataru.

Humanized anti–IFN-γ (HuZAF) in the treatment of psoriasis

Approaches to the diagnosis and management of patients with a history of nonsteroidal anti-inflammatory drug–related urticaria and angioedema Marek L.

Peanut-induced intestinal allergy is mediated through a mast cell–IgE–FcεRI–IL-13 pathway Meiqin Wang, MD, PhD, Katsuyuki Takeda, MD, PhD, Yoshiki Shiraishi,

Jon Genuneit, MD, MSc Journal of Allergy and Clinical Immunology

Toll-like receptor 2 is important for the TH1 response to cutaneous sensitization Haoli Jin, MD, PhD, Lalit Kumar, PhD, Clinton Mathias, PhD, David Zurakowski,

Sabine Leisten, MSc, Michiko K

Receptor-interacting protein kinase 3 controls keratinocyte activation in a necroptosis- independent manner and promotes psoriatic dermatitis in mice

Src homology 2 domain–containing inositol 5-phosphatase 1 deficiency leads to a spontaneous allergic inflammation in the murine lung Sun-Young Oh, PhD,

Histamine H4 receptor antagonists are superior to traditional antihistamines in the attenuation of experimental pruritus Paul J. Dunford, MSc, Kacy N.

Update on the role of prostaglandins in allergic lung inflammation: Separating friends from foes, harder than you might think Martin L. Moore, PhD, R.

Substance P activates Mas-related G protein–coupled receptors to induce itch Ehsan Azimi, MD, Vemuri B. Reddy, PhD, Paula Juliana Seadi Pereira, PhD,

Liam O’Mahony, PhD, Mübeccel Akdis, MD, PhD, Cezmi A. Akdis, MD

Attenuated neutrophil axis in atopic dermatitis compared to psoriasis reflects TH17 pathway differences between these diseases Nikhil Dhingra, BS, Mayte.

Evidence for an Age-Dependent Decline in Axon Regeneration in the Adult Mammalian Central Nervous System Cédric G. Geoffroy, Brett J. Hilton, Wolfram.

Autophagy: Nobel Prize 2016 and allergy and asthma research

IL-2– and CD25-dependent immunoregulatory mechanisms in the homeostasis of T-cell subsets Sven Létourneau, DPhil, Carsten Krieg, PhD, Giuseppe Pantaleo,

Lei Wang, MD, PhD, Jesse P. Joad, MD, Caiyun Zhong, MD, PhD, Kent E

The Janus kinase inhibitor JTE-052 improves skin barrier function through suppressing signal transducer and activator of transcription 3 signaling Wataru.

New pathways for itching in patients with atopic dermatitis?

Sara Paveglio, PhD, MS, Erin Bennett, MS, Kelly L. Hawley, PhD, Adam P

Evaluation and management of a patient with chronic pruritus

The steroidogenic enzyme Cyp11a1 is essential for development of peanut-induced intestinal anaphylaxis Meiqin Wang, MD, PhD, Julita Ramirez, DVM, PhD,

Anti–IL-5 therapy reduces mast cell and IL-9 cell numbers in pediatric patients with eosinophilic esophagitis Iris M. Otani, MD, Arjun A. Anilkumar,

Expression of chemokines and chemokine receptors in lesional and nonlesional upper skin of patients with atopic dermatitis Eva Gros, MSc, Caroline Bussmann,

Dorothea Dijkstra, MSc, Rob Leurs, PhD, Paul Chazot, PhD, Fiona C

The extra domain A of fibronectin is essential for allergen-induced airway fibrosis and hyperresponsiveness in mice Martin Kohan, MSc, Andres F. Muro,

Prostaglandin E2–EP3 signaling suppresses skin inflammation in murine contact hypersensitivity Tetsuya Honda, MD, PhD, Toshiyuki Matsuoka, MD, PhD, Mayumi.

Immunoglobulin-mediated CNS repair

Severe cutaneous human papillomavirus infection associated with natural killer cell deficiency following stem cell transplantation for severe combined.

Repeated low-dose intradermal allergen injection suppresses allergen-induced cutaneous late responses Giuseppina Rotiroti, MD, Mohamed Shamji, PhD, Stephen.

Interrupting IL-6–receptor signaling improves atopic dermatitis but associates with bacterial superinfection Alexander A. Navarini, MD, PhD, Lars E.

Possible new therapeutic strategy to regulate atopic dermatitis through upregulating filaggrin expression Atsushi Otsuka, MD, PhD, Hiromi Doi, MS, Gyohei.

Junqing Cui, PhD, Stephen Pazdziorko, Joy S

Large-scale gene expression profiling reveals distinct type 2 inflammatory patterns in chronic rhinosinusitis subtypes Matthew A. Tyler, MD, Chris B.

Natural history of cow’s milk allergy

Itching as a systemic disease

Presentation transcript:

Synergistic antipruritic effects of gamma aminobutyric acid A and B agonists in a mouse model of atopic dermatitis Ferda Cevikbas, PhD, Joao M. Braz, PhD, Xidao Wang, PhD, Carlos Solorzano, PhD, Mathias Sulk, MD, Timo Buhl, MD, Martin Steinhoff, PhD, Allan I. Basbaum, PhD Journal of Allergy and Clinical Immunology Volume 140, Issue 2, Pages 454-464.e2 (August 2017) DOI: 10.1016/j.jaci.2017.02.001 Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 Synergistic antipruritic interaction of GABA-A and GABA-B receptor agonists. A, Baclofen (Bac) ≥ 3.0 mg/kg or muscimol ≥ 1.5 mg/kg (red) are sedating. Nonsedative baclofen or muscimol against histamine- (B), chloroquine- (C), and endothelin-1 (D). Coadministering nonsedative baclofen and muscimol against histamine (B) and endothelin-1 (D). Combined subthreshold baclofen and ED50 muscimol against chloroquine (C). Data are means ± SEMs; **P < .005, ***P < .001; 2-way ANOVA. Bac 1.0, Baclofen 1.0 mg/kg; V, vehicle. Journal of Allergy and Clinical Immunology 2017 140, 454-464.e2DOI: (10.1016/j.jaci.2017.02.001) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 A synergistic interaction of GABA-A and GABA-B receptors is antipruritic against chronic itch. Compared with saline (black), systemic baclofen (red; A) or muscimol (B) in IL-31Tg mice is antipruritic. Systemic coadministration of subthreshold baclofen and muscimol (M) synergize against spontaneous scratching and these doses are not sedating (C). Data are means ± SEMs; **P < .005, ***P < .001; 2-way ANOVA. BL, Baseline. Journal of Allergy and Clinical Immunology 2017 140, 454-464.e2DOI: (10.1016/j.jaci.2017.02.001) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 Upregulation of propruritic and downregulation of antipruritic genes in the spinal cord of IL-31Tg mice. A-C, In IL-31Tg mice (red), spinal cord mRNA levels of the GABA-B1 receptor (B) decreased; GRP and PPTA mRNA (C) increased. Expression of GAD 65/67 (A), GABA-A receptor subunits (B), or GRPR and NK1 receptor (NK1R) (C) did not change. Data are means ± SEMs; *P < .05; ***P < .001; Student t test. NS, Not significant; WT, wild type. Journal of Allergy and Clinical Immunology 2017 140, 454-464.e2DOI: (10.1016/j.jaci.2017.02.001) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 Transplant-mediated reduction of scratching, skin lesions, and spinal cord activity in IL-31Tg mice. Skin lesions (A-I) and scratching (J) (n = 10 vs 9 controls) reduced only after MGE transplant. Data are means ± SEMs; *relative to baseline; #relative to control; *P < .05; **P < .005; ##P < .05; 2-way ANOVA and Bonferroni post hoc. K-O, MGE transplants reduced scratching-induced dorsal horn Fos+ neurons (N; red bar in O). Data are means ± SEM; *P < .05; Student t test. Bar = 100 μm. Journal of Allergy and Clinical Immunology 2017 140, 454-464.e2DOI: (10.1016/j.jaci.2017.02.001) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 5 MGE transplants ameliorate skin pathology. A-F, Scratching associated hyperparakeratosis, epidermal thickening (hyperplasia), and looser upper dermis (A, yellow arrows; E, n = 3) are reduced after MGE transplantation (B). Neither inflammatory infiltrate (A, B, E, n = 3) nor mast cell number differed in control (C, n = 3) and transplanted mice (D, F, n = 4). Data are means ± SEMs; ***P < .001; Student t test. Bar = 145 μm. Journal of Allergy and Clinical Immunology 2017 140, 454-464.e2DOI: (10.1016/j.jaci.2017.02.001) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 6 Spinal cord transplanted MGE cells differentiate into GABAergic interneurons. A-I, GFP+ (green) MGE cells survived in the spinal cord of IL-31Tg mice (A, D, G) and expressed markers of subpopulations of GABAergic interneurons, including GABA (B), parvalbumin (E), and neuropeptide Y (H). Merged imaged are shown in C, F, and I. Bar = 100 μm. Journal of Allergy and Clinical Immunology 2017 140, 454-464.e2DOI: (10.1016/j.jaci.2017.02.001) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E1 Transplanted GFP-expressing MGE cells (green) extend long processes (A), both caudal (B) and rostral (C) to and well beyond the injection sites. DH, Dorsal horn; VH, ventral horn. Bar = 300 μm in A and 100 μm in B and C. Journal of Allergy and Clinical Immunology 2017 140, 454-464.e2DOI: (10.1016/j.jaci.2017.02.001) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig E2 There is no difference in GAD65 or GAD67 expression levels between MGE- and medium-injected IL-31Tg mice (n = 5; Student t test). Journal of Allergy and Clinical Immunology 2017 140, 454-464.e2DOI: (10.1016/j.jaci.2017.02.001) Copyright © 2017 American Academy of Allergy, Asthma & Immunology Terms and Conditions