DOCSLIB.ORG

Targeting Key Proximal Drivers of Type 2 Inflammation in Disease

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
Targeting Key Proximal Drivers of Type 2 Inflammation in Disease REVIEWS Targeting key proximal drivers of type 2 inflammation in disease Namita A. Gandhi1, Brandy L. Bennett1, Neil M. H. Graham1, Gianluca Pirozzi2, Neil Stahl1 and George D. Yancopoulos1 | Abstract Systemic type 2 inflammation encompassing T helper 2 (TH2)-type responses is emerging as a unifying feature of both classically defined allergic diseases, such as asthma, and a range of other inflammatory diseases. Rather than reducing inflammation with broad-acting immunosuppressants or narrowly targeting downstream products of the TH2 pathway, such as immunoglobulin E (IgE), efforts to target the key proximal type 2 cytokines — interleukin‑4 (IL‑4), IL‑5 and IL‑13 — represent a promising strategy to achieve therapeutic benefit across multiple diseases. After several initial disappointing clinical results with therapies targeting IL‑4, IL‑5 or IL‑13 in asthma, applying a personalized approach achieved therapeutic benefit in an asthma subtype exhibiting an ‘allergic’ phenotype. More recently, efficacy was extended into a broad population of people with asthma. This argues that the Type 2 inflammation is broadly relevant across the severe asthma population if the key upstream drivers are properly blocked. Moreover, the simultaneous inhibition of IL‑4 and IL‑13 has shown significant clinical activity in diseases that are often co-morbid with asthma — atopic dermatitis and chronic sinusitis with nasal polyps — supporting the hypothesis that targeting a central ‘driver pathway’ could benefit multiple allergic diseases. Allergic diseases are increasingly becoming a global Although initial clinical studies using type 2 pathway epidemic. Epidemiological studies have demonstrated the modulators were somewhat disappointing, more recent increasing prevalence of food allergies, rhinoconjuncti­ clinical data in patients with allergic asthma (as iden­ vitis, atopic dermatitis and asthma1–3. Allergy is a systemic tified by biomarkers) have provided support for the type 2 inflammatory reaction (BOX 1) to an innocuous important roles of three particular type 2 cytokines: antigen (allergen) resulting from a complex interplay interleukin‑5 (IL‑5) and the sister cytokines IL‑4 and between genetic and environmental factors. This reaction IL‑13, which share a common receptor (FIG. 1). Treatment ultimately leads to increases in immunoglobulin E (IgE) with the IL‑5‑specific humanized monoclonal antibody production and various associated inflammatory immune (mAb) mepolizumab (developed by GlaxoSmithKline) responses. Patients may present with a wide range of demonstrated efficacy in a subset of patients with asthma disease severity, from mild to life-threatening, involving and chronic sinusitis with nasal polyps (CSwNP). In single or multiple organ systems and tissues. Allergic addition, simultaneous blockade of IL‑4 and IL‑13 diseases may appear disparate based on their distinct signalling using a fully human IL‑4 receptor subunit organ and tissue manifestations and are often treated by alpha (IL‑4Rα)-blocking antibody (dupilumab; devel­ 1Regeneron Pharmaceuticals, clinicians with different medical specialties. However, oped by Regeneron/Sanofi) has demonstrated clinical Tarrytown, New York the tendency for diverse allergic diseases to present as activity across three allergic diseases: atopic dermatitis, 10591, USA. co‑morbidities or progressively (that is, the ‘atopic march’) CSwNP, and asthma. These recent clinical data raise the 2Research and Development, Sanofi, Bridgewater, suggests that these diseases may share common under­ intriguing possibility that targeting a key central ‘driver New Jersey 08807, USA. lying drivers. Along these lines, it has long been recog­ pathway’ could have a substantial therapeutic effect on Correspondence to N.A.G. nized that the T helper 2 (TH2)-mediated responses of allergic diseases characterized by diverse organ-specific namita.gandhi@ type 2 inflammation are important in both asthma and clinical manifestations. Analogous to oncology — in regeneron.com atopic dermatitis, two highly prevalent chronic diseases which it is now recognized that it may be better to define doi:10.1038/nrd4624 with distinct tissue-specific manifestations in the lung and cancers based on their causative mutations rather than Published online 16 Oct 2015 skin, respectively. their tissue of origin for personalized treatment — it NATURE REVIEWS | DRUG DISCOVERY VOLUME 15 | JANUARY 2016 | 35 © 2016 Macmillan Publishers Limited. All rights reserved REVIEWS Box 1 | Type 2 immunity chronic idiopathic urticaria, CSwNP and eosinophilic oesophagitis. Here, we provide a review of recent mile­ Type 2 immunity refers to a specialized immune response involving the innate and the stone developments in clinical research that have led to adaptive arms of the immune system to promote barrier immunity on mucosal surfaces, a deeper understanding of the pathobiology of allergic in particular to eliminate parasitic pathogens. Type 2 immunity is characterized by T + diseases and provided support for the notion that the helper 2 (TH2) CD4 T cells and B cell production of the immunoglobulin E (IgE) antibody subclass. In addition, the innate cellular response includes group 2 innate lymphoid type 2 inflammatory cascade is a unifying feature of cells, eosinophils, basophils, mast cells and interleukin‑4 (IL-4)- and/or IL-13‑activated multiple diseases. macrophages. The response is associated with several cytokine mediators such as IL‑4, IL‑5, IL‑9 and IL‑13. Epithelial-derived cytokines, thymic stromal lymphopoietin Unmet need in severe allergic diseases (TSLP), IL‑25 and IL‑33 also propagate or initiate type 2 responses, but their functions Although some allergic diseases (such as allergic rhini­ are not limited to type 2 immune responses. This inflammatory response can also be tis) are well served with antihistamines and specific initiated in response to allergens, leading to allergic diseases. immunotherapy, nonspecific immunosuppression is the mainstay of therapy for more-severe allergic diseases such as atopic dermatitis and asthma. In both these may be time to define and group allergic diseases and diseases, aberrant inflammatory responses exacerbate­ thereby tailor therapy based on common immunological and propagate the disease symptoms. Reducing inflam­ pathways. mation by systemically administering broad-acting The predominance of type 2 inflammation is a key immunosuppressants such as oral or intravenous cor­ driver of allergic diseases4,5. The type of antigen, in ticosteroids, cyclosporin A, methotrexate, azathio­ combination with environmental factors and under­ prine or mycophenolate mofetil effectively alleviates lying genetics, influences the release of an array of symptoms of severe disease8. The immunosuppressive­ cytokines that results in the initiation or propagation of activity of these agents results from targeting down­ type 2 inflammatory processes by innate and lymphoid stream mediators such as transcription factors. For cells. At the barrier interface to environmental stimuli, example, corticosteroids bind glucocorticoid receptors epithelial-derived cytokines such as IL‑25, IL‑33 and and suppress the expression of key transcription factors thymic stromal lymphopoietin (TSLP) serve to initi­ that drive inflammation, such as nuclear factor-κB9. ate type 2 immune responses or amplify existing type 2 Cyclosporin A is a calcineurin inhibitor that prevents the inflammation. These upstream mediators stimulate production of IL‑2 (via the transcription factor nuclear innate cells to produce type 2 cytokines and also con­ factor of activated T cells (NFAT)), which is required for tribute to priming and polarizing naive T cells into CD4+ T cell activation and proliferation10. However, owing to 6,7 TH2 cells . TH lymphocyte subsets are classified based the broad mechanism of action of cyclosporin A and on the immune response associated with particular corticosteroids, systemic immunosuppressive therapies cytokines and inflammatory mediators specific to each result in pleiotropic effects that lead to toxicities such as subset. For example, interferon-γ (IFNγ) is produced by fluid retention, glucose intolerance, hypertension, muscle TH1 cells, IL‑4, IL‑5 and IL‑13 by TH2 cells, IL‑9 by TH9 weakness, gastrointestinal intolerance, potential bone cells, IL‑17A, IL‑17F, IL‑21 and IL‑22 by TH17 cells, IL‑22 loss, suppression of the hypothalamic–pituitary–adrenal 11,12 by TH22 cells, and IL‑10 by regulatory T cells. Among axis and increased susceptibility to infections . Local other roles, TH2 cells induce B cell proliferation and the administration (that is, inhaled drugs, topically applied subsequent production of antibodies that undergo iso­ drops, nasal sprays or creams) reduces the side effects of type switching, resulting in high levels of circulating these immunosuppressive agents; however, local immuno­ IgE (FIG. 2a). Thus, IgE is a key downstream biomarker suppression is not sufficient to treat the more severe forms of TH2 cell activation. IgE binds to the high-affinity IgE of these diseases. Thus, there remains a significant need receptor (FcεRI) found on basophils and mast cells, and for more-specific therapies. the crosslinking of IgE on these cells leads to cellular Applying a brute force approach to suppressing activation and the degranulation of several inflamma­ inflammation does not provide insight into which tory mediators. These inflammatory mediators include immune pathways propagate disease. For example, the histamine, prostaglandins
Load more

Recommended publications
  • Use of Mepolizumab in Adult Patients with Cystic Fibrosis and An
    Zhang et al. Allergy Asthma Clin Immunol (2020) 16:3 Allergy, Asthma & Clinical Immunology https://doi.org/10.1186/s13223-019-0397-3 CASE REPORT Open Access Use of mepolizumab in adult patients with cystic fbrosis and an eosinophilic phenotype: case series Lijia Zhang1, Larry Borish2,3, Anna Smith2, Lindsay Somerville2 and Dana Albon2* Abstract Background: Cystic fbrosis (CF) is characterized by infammation, progressive lung disease, and respiratory failure. Although the relationship is not well understood, patients with CF are thought to have a higher prevalence of asthma than the general population. CF Foundation (CFF) annual registry data in 2017 reported a prevalence of asthma in CF of 32%. It is difcult to diferentiate asthma from CF given similarities in symptoms and reversible obstructive lung function in both diseases. However, a specifc asthma phenotype (type 2 infammatory signature), is often identifed in CF patients and this would suggest potential responsiveness to biologics targeting this asthma phenotype. A type 2 infammatory condition is defned by the presence of an interleukin (IL)-4high, IL-5high, IL-13high state and is suggested by the presence of an elevated total IgE, specifc IgE sensitization, or an elevated absolute eosinophil count (AEC). In this manuscript we report the efects of using mepolizumab in patients with CF and type 2 infammation. Results: We present three patients with CF (63, 34 and 24 year of age) and personal history of asthma, who displayed signifcant eosinophilic infammation and high total serum IgE concentrations (type 2 infammation) who were treated with mepolizumab. All three patients were colonized with multiple organisms including Pseudomonas aeruginosa and Aspergillus fumigatus and tested positive for specifc IgE to multiple allergens.
    [Show full text]
  • Type 2 Immunity in Tissue Repair and Fibrosis
    REVIEWS Type 2 immunity in tissue repair and fibrosis Richard L. Gieseck III1, Mark S. Wilson2 and Thomas A. Wynn1 Abstract | Type 2 immunity is characterized by the production of IL‑4, IL‑5, IL‑9 and IL‑13, and this immune response is commonly observed in tissues during allergic inflammation or infection with helminth parasites. However, many of the key cell types associated with type 2 immune responses — including T helper 2 cells, eosinophils, mast cells, basophils, type 2 innate lymphoid cells and IL‑4- and IL‑13‑activated macrophages — also regulate tissue repair following injury. Indeed, these cell populations engage in crucial protective activity by reducing tissue inflammation and activating important tissue-regenerative mechanisms. Nevertheless, when type 2 cytokine-mediated repair processes become chronic, over-exuberant or dysregulated, they can also contribute to the development of pathological fibrosis in many different organ systems. In this Review, we discuss the mechanisms by which type 2 immunity contributes to tissue regeneration and fibrosis following injury. Type 2 immunity is characterized by increased pro‑ disorders remain unclear, although persistent activation duction of the cytokines IL‑4, IL‑5, IL‑9 and IL‑13 of tissue repair pathways is a major contributing mech‑ (REF. 1) . The T helper 1 (TH1) and TH2 paradigm was anism in most cases. In this Review, we provide a brief first described approximately three decades ago2, and overview of fibrotic diseases that have been linked to for many of the intervening years, type 2 immunity activation of type 2 immunity, discuss the various mech‑ was largely considered as a simple counter-­regulatory anisms that contribute to the initiation and maintenance mechanism controlling type 1 immunity3 (BOX 1).
    [Show full text]
  • Atopic Dermatitis: an Expanding Therapeutic Pipeline for a Complex Disease
    REVIEWS Atopic dermatitis: an expanding therapeutic pipeline for a complex disease Thomas Bieber 1,2,3 Abstract | Atopic dermatitis (AD) is a common chronic inflammatory skin disease with a complex pathophysiology that underlies a wide spectrum of clinical phenotypes. AD remains challenging to treat owing to the limited response to available therapies. However, recent advances in understanding of disease mechanisms have led to the discovery of novel potential therapeutic targets and drug candidates. In addition to regulatory approval for the IL-4Ra inhibitor dupilumab, the anti- IL-13 inhibitor tralokinumab and the JAK1/2 inhibitor baricitinib in Europe, there are now more than 70 new compounds in development. This Review assesses the various strategies and novel agents currently being investigated for AD and highlights the potential for a precision medicine approach to enable prevention and more effective long-term control of this complex disease. Atopic disorders Atopic dermatitis (AD) is the most common chronic inhibitors tacrolimus and pimecrolimus and more 1,2 A group of disorders having in inflammatory skin disease . About 80% of disease cases recently the phosphodiesterase 4 (PDE4) inhibitor cris- common a genetic tendency to typically start in infancy or childhood, with the remain- aborole. For the more severe forms of AD, besides the develop IgE- mediated allergic der developing during adulthood. Whereas the point use of ultraviolet light, current therapeutic guidelines reactions. These are atopic dermatitis, food allergy, allergic prevalence in children varies from 2.7% to 20.1% across suggest ciclosporin A, methotrexate, azathioprine and 3,4 rhino- conjunctivitis and countries, it ranges from 2.1% to 4.9% in adults .
    [Show full text]
  • The Role of Dupilumab in Severe Asthma
    biomedicines Review The Role of Dupilumab in Severe Asthma Fabio Luigi Massimo Ricciardolo * , Francesca Bertolini and Vitina Carriero Department of Clinical and Biological Sciences, University of Turin, San Luigi Gonzaga University Hospital, Orbassano, 10043 Turin, Italy; [email protected] (F.B.); [email protected] (V.C.) * Correspondence: [email protected]; Tel.: +39-0119026777 Abstract: Dupilumab is a fully humanized monoclonal antibody, capable of inhibiting intracellular signaling of both interleukin (IL)-4 and IL-13. These are two molecules that, together with other proinflammatory cytokines such as IL-5 and eotaxins, play a pivotal role in orchestrating the airway inflammatory response defined as Type 2 (T2) inflammation, driven by Th2 or Type 2 innate lymphoid cells, which is the major feature of the T2 high asthma phenotype. The dual inhibition of IL-4 and IL-13 activities is due to the blockade of type II IL-4 receptor through the binding of dupilumab with the subunit IL-4Rα. This results in the repression of STAT6 and in the suppression of subsequent de novo formation of several molecules involved in the T2 inflammatory signature. Several clinical trials tested the efficacy and safety of dupilumab in large populations of uncontrolled severe asthmatics, revealing significant improvements in lung function, asthma control, and exacerbation rate. Similar results were reported when dupilumab was employed in patients harboring pathogenetic processes related to T2 immune response, such as atopic dermatitis and chronic rhinosinusitis. In this review, we provide an overview of the recent research in the field of respiratory medicine about dupilumab mechanism of action and its effects.
    [Show full text]
  • The Use of Biologics for Immune Modulation in Allergic Disease
    The use of biologics for immune modulation in allergic disease Willem van de Veen, Mübeccel Akdis J Clin Invest. 2019;129(4):1452-1462. https://doi.org/10.1172/JCI124607. Review Series The rising prevalence of allergies represents an increasing socioeconomic burden. A detailed understanding of the immunological mechanisms that underlie the development of allergic disease, as well as the processes that drive immune tolerance to allergens, will be instrumental in designing therapeutic strategies to treat and prevent allergic disease. Improved characterization of individual patients through the use of specific biomarkers and improved definitions of disease endotypes are paving the way for the use of targeted therapeutic approaches for personalized treatment. Allergen-specific immunotherapy and biologic therapies that target key molecules driving the Th2 response are already used in the clinic, and a wave of novel drug candidates are under development. In-depth analysis of the cells and tissues of patients treated with such targeted interventions provides a wealth of information on the mechanisms that drive allergies and tolerance to allergens. Here, we aim to deliver an overview of the current state of specific inhibitors used in the treatment of allergy, with a particular focus on asthma and atopic dermatitis, and provide insights into the roles of these molecules in immunological mechanisms of allergic disease. Find the latest version: https://jci.me/124607/pdf REVIEW SERIES: ALLERGY The Journal of Clinical Investigation Series Editor: Kari Nadeau The use of biologics for immune modulation in allergic disease Willem van de Veen1,2 and Mübeccel Akdis1 1Swiss Institute of Allergy and Asthma Research (SIAF), University of Zurich, Davos, Switzerland.
    [Show full text]
  • Type 2 Inflammation in Asthma
    Type 2 Inflammation in Asthma New Insights and Treatment Options This educational activity is sponsored by Postgraduate Healthcare Education, LLC and supported by an educational grant from Genzyme Corporation, Inc. Faculty Dennis M. Williams, PharmD, BCPS, AE-C Associate Professor and Vice Chair for Professional Education and Practice Division of Pharmacotherapy and Experimental Therapeutics University of North Carolina, Eshelman School of Pharmacy Chapel Hill, NC Dr. Williams is Associate Professor and Vice Chair for Professional Education and Practice at the Eshelman School of Pharmacy at the University of North Carolina (UNC) in Chapel Hill and a Clinical Specialist in Pulmonary Medicine at UNC Hospitals. He received his BS in Pharmacy and PharmD degrees from the University of Kentucky and is a Board Certified Pharmacotherapy Specialist and Certified Asthma Educator. He serves as a member of the Pharmaceutical Specialties Council: Infectious Diseases Pharmacotherapy and the National Asthma Educator Certification Board. His clinical teaching, research, and practice interests are related to lung diseases and their management. Disclosures Dr. Williams reports that his spouse is an employee of GlaxoSmithKline and owns stock in that company. The clinical reviewer, Matthew Casciano, PharmD, BCPS, has no actual or potential conflict of interest in relation to this program. Susanne Batesko, RN, BSN, Gary Gyss, and Susan R. Grady, MSN, RN-BC, as well as the planners, managers, and other individuals, not previously disclosed, who are in a position to control the content of Postgraduate Healthcare Education (PHE) continuing education activities hereby state that they have no relevant conflicts of interest and no financial relationships or relationships to products or devices during the past 12 months to disclose in relation to this activity.
    [Show full text]
  • A Review on the Effect of COVID-19 in Type 2 Asthma and Its Management
    International Immunopharmacology 91 (2021) 107309 Contents lists available at ScienceDirect International Immunopharmacology journal homepage: www.elsevier.com/locate/intimp Review A review on the effect of COVID-19 in type 2 asthma and its management Srijit Ghosh a,1, Srijita Das b, Rupsa Mondal a, Salik Abdullah a, Shirin Sultana a, Sukhbir Singh c, Aayush Sehgal c, Tapan Behl c,*,1 a Guru Nanak Institute of Pharmaceutical Science and Technology, Panihati, Sodepur, Kolkata 700114, West Bengal, India b Department of Pharmaceutical Sciences and Technology, Birla Institute of Technology, Mesra, Ranchi 835215, Jharkhand, India c Chitkara College of Pharmacy, Chitkara University, Patiala 140401, Punjab, India ARTICLE INFO ABSTRACT Keywords: Background: COVID-19 is considered the most critical health pandemic of 21st century. Due to extremely high COVID-19 transmission rate, people are more susceptible to viral infection. COVID-19 patients having chronic type-2 SARS-CoV-2 asthma prevails a major risk as it may aggravate the disease and morbidities. Type-2 asthma Objective: The present review mainly focuses on correlating the influence of COVID-19 in type-2 asthmatic pa­ Cytokines tients. Besides, it delineates the treatment measures and drugs that can be used to manage mild, moderate, and Inflammation T-cells severe symptoms of COVID-19 in asthmatic patients, thus preventing any exacerbation. Methods: An in-depth research was carried out from different peer-reviewed articles till September 2020 from several renowned databases like PubMed, Frontier, MEDLINE, and related websites like WHO, CDC, MOHFW, and the information was analysed and written in a simplified manner. Results: The progressive results were quite conflictingas severe cases of COVID-19 shows an increase in the level of several cytokines that can augment inflammation to the bronchial tracts, worsening the asthma attacks.
    [Show full text]
  • Understanding the Key Issues in the Treatment of Uncontrolled Persistent Asthma with Type 2 Inflammation
    EUROPEAN RESPIRATORY JOURNAL REVIEW W.W. BUSSE ET AL. Understanding the key issues in the treatment of uncontrolled persistent asthma with type 2 inflammation William W. Busse1, Monica Kraft2, Klaus F. Rabe3,4, Yamo Deniz5, Paul J. Rowe6, Marcella Ruddy5 and Mario Castro7 1UW Allergy, Pulmonary and Critical Care Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, USA. 2University of Arizona Health Sciences Center, Tucson, AZ, USA. 3LungenClinic Grosshansdorf (member of the German Center for Lung Research, DZL), Airway Research Center North (ARCN), Grosshansdorf, Germany. 4Christian-Albrechts University (member of the German Center for Lung Research, DZL), Airway Research Center North (ARCN), Kiel, Germany. 5Regeneron Pharmaceuticals, Inc., Tarrytown, NY, USA. 6Sanofi, Bridgewater, NJ, USA. 7University of Kansas School of Medicine, Kansas City, KS, USA. Corresponding author: William W. Busse ([email protected]) Shareable abstract (@ERSpublications) This review covers the pathophysiology of type 2 inflammation in asthma, its influence on type 2 comorbidities, and ways in which type 2 biomarkers can be harnessed to improve diagnosis and further personalise treatments in the age of biologic medicines https://bit.ly/2MSOI2O Cite this article as: Busse WW, Kraft M, Rabe KF, et al. Understanding the key issues in the treatment of uncontrolled persistent asthma with type 2 inflammation. Eur Respir J 2021; 58: 2003393 [DOI: 10.1183/13993003.03393-2020]. Abstract Copyright ©The authors 2021. Asthma is a complex respiratory disease that varies in severity and response to treatment. Several asthma phenotypes with unique clinical and inflammatory characteristics have been identified. Endotypes, based This version is distributed under the terms of the Creative on distinct molecular profiles, help to further elucidate the heterogeneity within asthma.
    [Show full text]
  • New Dupixent® (Dupilumab) Data Showcasing Improvements Across Four Type 2 Inflammatory Diseases to Be Presented at 2021 AAAAI Annual Meeting
    New Dupixent® (dupilumab) Data Showcasing Improvements Across Four Type 2 Inflammatory Diseases to be Presented at 2021 AAAAI Annual Meeting February 1, 2021 TARRYTOWN, N.Y. and PARIS, Feb. 1, 2021 /PRNewswire/ -- Improvements were noted across key disease measures in certain patients with asthma, atopic dermatitis, eosinophilic esophagitis and chronic rhinosinusitis with nasal polyposis New analyses build on a robust body of evidence reinforcing the role of Dupixent in certain diseases driven by type 2 inflammation Regeneron Pharmaceuticals, Inc. (NASDAQ: REGN) and Sanofi today announced new data further examining Dupixent® (dupilumab) in diseases driven by type 2 inflammation including atopic dermatitis, asthma, chronic rhinosinusitis with nasal polyposis (CRSwNP) and eosinophilic esophagitis. These data will be presented at the American Academy of Allergy, Asthma and Immunology (AAAAI) Virtual Annual Meeting, taking place from February 26 to March 1. Abstracts have been published in an online supplement to The Journal of Allergy and Clinical Immunology (JACI) and include: Atopic Dermatitis New analyses evaluate the efficacy of Dupixent in children with severe atopic dermatitis with atopic comorbidities. Oral Abstract 461A (February 27, 5:10 pm - 6:25 pm ET): Dupilumab Improves Signs and Symptoms of Severe Atopic Dermatitis in Children Aged 6–11 Years With and Without Comorbid Allergic Rhinitis, Lisa Beck Poster 99: Dupilumab Improves Signs and Symptoms of Severe Atopic Dermatitis in Children Aged 6–11 Years With and Without Comorbid Asthma, Mark Boguniewicz Asthma New analyses evaluate the efficacy of Dupixent in moderate-to-severe asthma patients with an allergic phenotype over the long-term, as well as difficult-to-treat patients.
    [Show full text]
  • The Regulation and Function of Thymic Stromal Lymphopoietin Receptor (TSLPR)
    The Regulation and Function of Thymic Stromal Lymphopoietin Receptor (TSLPR) in the Airway Epithelium Michael Miles Miazgowicz A dissertation submitted in partial fulfillment of the requirements for the degree of Doctor of Philosophy University of Washington 2013 Reading Committee: Steven F. Ziegler, Chair Joan M. Goverman Daniel J. Campbell Program Authorized to Offer Degree: Department of Immunology © Copyright 2013 Michael Miles Miazgowicz University of Washington Abstract The Regulation and Function of Thymic Stromal Lymphopoietin Receptor (TSLPR) in the Airway Epithelium Michael Miles Miazgowicz Chair of the Supervisory Committee: Affiliate Professor Steven F. Ziegler Department of Immunology The epithelially-derived cytokine thymic stromal lymphopoietin (TSLP) plays a key role in the development and progression of allergic disease and has notably been shown to directly promote the inflammatory responses that characterize asthma. Current models suggest that TSLP is produced by epithelial cells in response to inflammatory stimuli and acts upon hematopoietic cells to effect a TH2-type inflammatory response. Recent reports, however, have shown that epithelial cells themselves are capable of expressing the TSLP receptor (TSLPR), and may thus directly contribute to a TSLP- dependent response. In this thesis, we review what is known about both the immunological and epithelial responses that contribute to the pathogenesis of asthma, and further present novel data indicating a role for epithelially expressed TSLPR to play in those responses. We present data that epithelial cells indeed express a glycosylated form of the TSLP receptor. Furthermore, we find that beyond simply expressing TSLPR, epithelial cells are capable of dynamically regulating TSLPR in response to the same inflammatory cues that drive the production of TSLP.
    [Show full text]
  • Efficacy and Safety of Lebrikizumab
    King’s Research Portal DOI: 10.1016/j.jaad.2018.01.017 Document Version Publisher's PDF, also known as Version of record Link to publication record in King's Research Portal Citation for published version (APA): Simpson, E. L., Flohr, C., Eichenfield, L. F., Bieber, T., Sofen, H., Taïeb, A., Owen, R., Putnam, W., Castro, M., DeBusk, K., Lin, C-Y., Voulgari, A., Yen, K., & Omachi, T. A. (2018). Efficacy and safety of lebrikizumab (an anti- IL-13 monoclonal antibody) in adults with moderate-to-severe atopic dermatitis inadequately controlled by topical corticosteroids: A randomized, placebo-controlled phase II trial (TREBLE). Journal of the American Academy of Dermatology , 863-871.e11. https://doi.org/10.1016/j.jaad.2018.01.017 Citing this paper Please note that where the full-text provided on King's Research Portal is the Author Accepted Manuscript or Post-Print version this may differ from the final Published version. If citing, it is advised that you check and use the publisher's definitive version for pagination, volume/issue, and date of publication details. And where the final published version is provided on the Research Portal, if citing you are again advised to check the publisher's website for any subsequent corrections. General rights Copyright and moral rights for the publications made accessible in the Research Portal are retained by the authors and/or other copyright owners and it is a condition of accessing publications that users recognize and abide by the legal requirements associated with these rights. •Users may download and print one copy of any publication from the Research Portal for the purpose of private study or research.
    [Show full text]
  • Alternative Splicing of Interleukin-33 and Type 2 Inflammation in Asthma
    Alternative splicing of interleukin-33 and type 2 inflammation in asthma Erin D. Gordona,1, Laura J. Simpsonb, Cydney L. Riosc, Lando Ringelc, Marrah E. Lachowicz-Scrogginsd, Michael C. Petersa, Agata Wesolowska-Andersenc, Jeanmarie R. Gonzalezb, Hannah J. MacLeodd, Laura S. Christianb, Shaopeng Yuand, Liam Barryd, Prescott G. Woodruffa,e, K. Mark Anselb,e, Karl Nockaf, Max A. Seiboldc,g,h,2, and John V. Fahya,d,e,1,2 aDepartment of Pulmonary and Critical Care Medicine, University of California, San Francisco, CA 94143; bDepartment of Microbiology and Immunology, University of California San Francisco, CA 94143; cCenter for Genes, Environment, and Health, National Jewish Health, Denver, CO 80206; dCardiovascular Research Institute, University of California, San Francisco, CA 94143; eSandler Asthma Basic Research Center, University of California, San Francisco, CA 94143; fImmunoscience, Pfizer Worldwide Research and Development, Cambridge, MA 02139; gDepartment of Pediatrics, National Jewish Health, Denver, CO 80206; and hDivision of Pulmonary Sciences and Critical Care Medicine, Department of Medicine, Anschutz Medical Campus, University of Colorado, Aurora, CO 80045 Edited by Robert L. Coffman, Dynavax Technologies, Berkeley, CA, and approved June 10, 2016 (received for review February 3, 2016) Type 2 inflammation occurs in a large subgroup of asthmatics, and dependent on increases in intracellular calcium concentrations, novel cytokine-directed therapies are being developed to treat this which can be induced by exogenous ATP administration (22–24). population. In mouse models, interleukin-33 (IL-33) activates lung Moreover, it is not yet clear which cell type responds to IL-33 to resident innate lymphoid type 2 cells (ILC2s) to initiate airway type 2 sustain persistent type 2 inflammation in the airway.
    [Show full text]