DOCSLIB.ORG

A New Perspective for Biological Therapies of Severe Asthma

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
A New Perspective for Biological Therapies of Severe Asthma biomedicines Review Monoclonal Antibodies Targeting Alarmins: A New Perspective for Biological Therapies of Severe Asthma Corrado Pelaia 1,* , Giulia Pelaia 2, Federico Longhini 2 , Claudia Crimi 3 , Cecilia Calabrese 4, Luca Gallelli 1 , Angela Sciacqua 2 and Alessandro Vatrella 5 1 Department of Health Sciences, University “Magna Graecia” of Catanzaro, Viale Europa-Località Germaneto, 88100 Catanzaro, Italy; [email protected] 2 Department of Medical and Surgical Sciences, University “Magna Graecia” of Catanzaro, 88100 Catanzaro, Italy; [email protected] (G.P.); [email protected] (F.L.); [email protected] (A.S.) 3 Department of Clinical and Experimental Medicine, University of Catania, 95131 Catania, Italy; [email protected] 4 Department of Translational Medical Sciences, University of Campania “Luigi Vanvitelli”, 80131 Naples, Italy; [email protected] 5 Department of Medicine, Surgery, and Dentistry, University of Salerno, 84084 Salerno, Italy; [email protected] * Correspondence: [email protected]; Tel.: +39-0961-3647007; Fax: +39-0961-3647193 Abstract: Alarmins are innate cytokines, including thymic stromal lymphopoietin (TSLP), interleukin- 33 (IL-33), and interleukin-25 (IL-25), which are mainly produced by airway epithelium and exert a prominent role in asthma pathobiology. In particular, several environmental factors such as allergens, cigarette smoking, airborne pollutants, and infectious agents trigger the release of alarmins, which in turn act as upstream activators of pro-inflammatory pathways underlying type 2 (T2-high) asthma. Citation: Pelaia, C.; Pelaia, G.; Indeed, alarmins directly activate group 2 innate lymphoid cells (ILC2), eosinophils, basophils, and Longhini, F.; Crimi, C.; Calabrese, C.; mast cells and also stimulate dendritic cells to drive the commitment of naïve T helper (Th) cells Gallelli, L.; Sciacqua, A.; Vatrella, A. Monoclonal Antibodies Targeting towards the Th2 immunophenotype. Therefore, TSLP, IL-33, and IL-25 represent suitable targets Alarmins: A New Perspective for for add-on therapies of severe asthma. Within this context, the fully human anti-TSLP monoclonal Biological Therapies of Severe antibody tezepelumab has been evaluated in very promising randomized clinical trials. Tezepelumab Asthma. Biomedicines 2021, 9, 1108. and other anti-alarmins are thus likely to become, in the near future, valuable therapeutic options for https://doi.org/10.3390/ the biological treatment of uncontrolled severe asthma. biomedicines9091108 Keywords: asthma; TSLP; IL-33; IL-25; tezepelumab; anti-alarmins Academic Editors: Hiroshi Wakao and Berislav Bošnjak Received: 18 July 2021 1. Introduction Accepted: 26 August 2021 Published: 29 August 2021 Asthma is a chronic inflammatory disease of the respiratory tract, usually characterized by variable airflow limitation and affecting more than 300 million people worldwide [1,2]. Publisher’s Note: MDPI stays neutral Asthma phenotypes are heterogeneous and include eosinophilic patterns, underpinned by either with regard to jurisdictional claims in allergic or non-allergic mechanisms, as well as neutrophilic and paucigranulocytic traits [3–5]. published maps and institutional affil- Eosinophilic asthma is driven by complex cellular and molecular pathways which shape the iations. so-called type 2 (T2-high) airway inflammation, a term based on the key pathogenic roles played by T helper 2 (Th2) lymphocytes and group 2 innate lymphoid cells (ILC2), releasing the interleukins 4 (IL-4), 5 (IL-5), 9 (IL-9), and 13 (IL-13) [6–8]. Within this pathobiological context, the bronchial epithelium exerts pivotal functions by producing three innate cytokines named alarmins, which include thymic stromal lymphopoietin (TSLP), interleukin-33 (IL-33), and Copyright: © 2021 by the authors. Licensee MDPI, Basel, Switzerland. interleukin-25 (IL-25) [9–11]. The secretion of these cytokines occurs when airway epithelial cells This article is an open access article undergo injuries caused by several environmental triggers such as allergens, respiratory viruses, distributed under the terms and bacteria, cigarette smoking, and airborne pollutants (Figure1) [ 12]. Therefore, TSLP,IL-33, and conditions of the Creative Commons IL-25 provide alarm signals which solicit the immune system to react to bronchial epithelial Attribution (CC BY) license (https:// damage [9]. As a consequence, these alarmins behave as upstream activators of both innate and creativecommons.org/licenses/by/ adaptive immune responses involved in type 2 asthma (Figure1). Indeed, alarmins are able to 4.0/). induce conventional dendritic cells to drive the differentiation and expansion of Th2 cells, as Biomedicines 2021, 9, 1108. https://doi.org/10.3390/biomedicines9091108 https://www.mdpi.com/journal/biomedicines Biomedicines 2021, 9, x FOR PEER REVIEW 2 of 15 1) [12]. Therefore, TSLP, IL-33, and IL-25 provide alarm signals which solicit the immune Biomedicines 2021, 9system, 1108 to react to bronchial epithelial damage [9]. As a consequence, these alarmins 2 of 15 behave as upstream activators of both innate and adaptive immune responses involved in type 2 asthma (Figure 1). Indeed, alarmins are able to induce conventional dendritic cells to drive the differentiation and expansion of Th2 cells, as well as to directly promote ILC2 activationwell and as proliferation to directly promote [13]. Moreover, ILC2 activation by stimulating and proliferation the commitment [13]. Moreover, of naïve by stimulating the Th lymphocytescommitment towards the of Th17 naïve cellular Th lymphocytes immunophenotype, towards the Th17 TSLP cellular can also immunophenotype, contribute TSLP can to the pathogenesisalso contribute of T2-low to neutrophilic the pathogenesis asthma of T2-low[14]. neutrophilic asthma [14]. Figure 1. PathogenicFigure 1. Pathogenic actions of alarmins actions of in alarmins type 2 asthma. in type As 2 aasthma. result ofAs injuries a result caused of injuries by several caused noxious by several agents, airway epithelial cellsnoxious release agents, alarmins airway (TSLP, epithelial IL-33, andcells IL-25).release Thesealarmins cytokines (TSLP, induce IL-33, theand activationIL-25). These of the cytokines adaptive immune induce the activation of the adaptive immune system, thus driving dendritic cell-mediated system, thus driving dendritic cell-mediated differentiation of Th2 lymphocytes, leading to B cell-dependent production of differentiation of Th2 lymphocytes, leading to B cell-dependent production of immunoglobulins E immunoglobulins E (IgE). Alarmins also elicit innate immune responses by directly stimulating group 2 innate lymphoid (IgE). Alarmins also elicit innate immune responses by directly stimulating group 2 innate lymphoid cells (ILC2),cells eosinophils, (ILC2), eosinophils, basophils, andbasophils, mast cells. and Uponmast cells activation. Upon induced activation by induce alarmins,d by Th2 alarmins, and ILC2 Th2 cells and release high amounts ofILC2 IL-4, cells IL-5, release and IL-13. high This amounts original of figureIL-4, IL-5, was createdand IL-13. by theThis authors original using figure “BioRender.com” was created by (accessedthe on 8 August 2021).authors using “BioRender.com”(accessed on 8 August 2021). Because of theirBecause relevant of pathogenic their relevant functi pathogenicons, alarmins functions, represent alarmins suitable represent molecular suitable molecular targets for emergingtargets biological for emerging therapies biological of asthma therapies [15–20]. of asthma In particular, [15–20]. In neutralization particular, neutralization of of alarmins viaalarmins specific viaantibodies specific potentiall antibodiesy potentiallyprovides an provides effective an therapeutic effective therapeutic strategy strategy capa- capable of interferingble of interfering at a very at upstream a very upstream level with level the with complex the complex immunopathologic immunopathologic cascades cascades leadingleading to type to type2 asthma. 2 asthma. In fact, In fact, this this approach approach can can impact impact more more broadly broadly on on asthma patho- asthma pathobiologybiology withwith respect respect to currentto current downstream downstream therapies therapies targeting circumscribedtargeting pathways circumscribed mediatedpathways bymediated single cytokinesby single cytokines (IL-4, IL-5, (IL-4, and IL-5, IL-13) and or receptorsIL-13) or receptors (IL-4 receptor and IL-5 (IL-4 receptor andreceptor) IL-5 receptor) [21]. Among [21]. anti-alarmins, Among anti-alarmins, the most studiedthe most anti-TSLP studied anti-TSLP monoclonal antibody in monoclonal antibodyclinical trialsin clinical is tezepelumab trials is [20 ,tezepelumab22,23]; some anti-IL-33[20,22,23]; antibodies some anti-IL-33 are under investigation, whereas no anti-IL-25 drug has entered clinical evaluation so far [18]. In this regard, it antibodies are under investigation, whereas no anti-IL-25 drug has entered clinical is noteworthy that anti-alarmins could induce effective therapeutic benefits for patients evaluation so far [18]. In this regard, it is noteworthy that anti-alarmins could induce with uncontrolled T2-high asthma by lowering disease exacerbations, as well as by im- effective therapeutic benefits for patients with uncontrolled T2-high asthma by lowering proving symptom control, lung function, quality of life, and oral corticosteroid (OCS) disease exacerbations, as well as by improving symptom control, lung function, quality of dependence [18,20].
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]
  • Targeting Tgfβ Signal Transduction for Cancer Therapy
    Signal Transduction and Targeted Therapy www.nature.com/sigtrans REVIEW ARTICLE OPEN Targeting TGFβ signal transduction for cancer therapy Sijia Liu1, Jiang Ren1 and Peter ten Dijke1 Transforming growth factor-β (TGFβ) family members are structurally and functionally related cytokines that have diverse effects on the regulation of cell fate during embryonic development and in the maintenance of adult tissue homeostasis. Dysregulation of TGFβ family signaling can lead to a plethora of developmental disorders and diseases, including cancer, immune dysfunction, and fibrosis. In this review, we focus on TGFβ, a well-characterized family member that has a dichotomous role in cancer progression, acting in early stages as a tumor suppressor and in late stages as a tumor promoter. The functions of TGFβ are not limited to the regulation of proliferation, differentiation, apoptosis, epithelial–mesenchymal transition, and metastasis of cancer cells. Recent reports have related TGFβ to effects on cells that are present in the tumor microenvironment through the stimulation of extracellular matrix deposition, promotion of angiogenesis, and suppression of the anti-tumor immune reaction. The pro-oncogenic roles of TGFβ have attracted considerable attention because their intervention provides a therapeutic approach for cancer patients. However, the critical function of TGFβ in maintaining tissue homeostasis makes targeting TGFβ a challenge. Here, we review the pleiotropic functions of TGFβ in cancer initiation and progression, summarize the recent clinical advancements regarding TGFβ signaling interventions for cancer treatment, and discuss the remaining challenges and opportunities related to targeting this pathway. We provide a perspective on synergistic therapies that combine anti-TGFβ therapy with cytotoxic chemotherapy, targeted therapy, radiotherapy, or immunotherapy.
    [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]
  • Expression of the Tumor Necrosis Factor Receptor-Associated Factors
    Expression of the Tumor Necrosis Factor Receptor- Associated Factors (TRAFs) 1 and 2 is a Characteristic Feature of Hodgkin and Reed-Sternberg Cells Keith F. Izban, M.D., Melek Ergin, M.D, Robert L. Martinez, B.A., HT(ASCP), Serhan Alkan, M.D. Department of Pathology, Loyola University Medical Center, Maywood, Illinois the HD cell lines. Although KMH2 showed weak Tumor necrosis factor receptor–associated factors expression, the remaining HD cell lines also lacked (TRAFs) are a recently established group of proteins TRAF5 protein. These data demonstrate that consti- involved in the intracellular signal transduction of tutive expression of TRAF1 and TRAF2 is a charac- several members of the tumor necrosis factor recep- teristic feature of HRS cells from both patient and tor (TNFR) superfamily. Recently, specific members cell line specimens. Furthermore, with the excep- of the TRAF family have been implicated in promot- tion of TRAF1 expression, HRS cells from the three ing cell survival as well as activation of the tran- HD cell lines showed similar TRAF protein expres- ␬ scription factor NF- B. We investigated the consti- sion patterns. Overall, these findings demonstrate tutive expression of TRAF1 and TRAF2 in Hodgkin the expression of several TRAF proteins in HD. Sig- and Reed–Sternberg (HRS) cells from archived nificantly, the altered regulation of selective TRAF paraffin-embedded tissues obtained from 21 pa- proteins may reflect HRS cell response to stimula- tients diagnosed with classical Hodgkin’s disease tion from the microenvironment and potentially (HD). In a selective portion of cases, examination of contribute both to apoptosis resistance and cell HRS cells for Epstein-Barr virus (EBV)–encoded maintenance of HRS cells.
    [Show full text]
  • TRAF5, a Novel Tumor Necrosis Factor Receptor-Associated Factor Family
    Proc. Natl. Acad. Sci. USA Vol. 93, pp. 9437-9442, September 1996 Biochemistry TRAF5, a novel tumor necrosis factor receptor-associated factor family protein, mediates CD40 signaling (signal transduction/protein-protein interaction/yeast two-hybrid system) TAKAoMI ISHIDA*, TADASHI ToJo*, TSUTOMU AOKI*, NORIHIKO KOBAYASHI*, TSUKASA OHISHI*, TOSHIKI WATANABEt, TADASHI YAMAMOTO*, AND JUN-ICHIRO INOUE*t Departments of *Oncology and tPathology, The Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo 108, Japan Communicated by David Baltimore, Massachusetts Institute of Technology, Cambridge, MA, May 22, 1996 (received for review March 8, 1996) ABSTRACT Signals emanating from CD40 play crucial called a death domain, suggesting that these receptors could roles in B-cell function. To identify molecules that transduce have either common or similar signaling mechanisms (13). CD40 signalings, we have used the yeast two-hybrid system to Biochemical purification of receptor-associated proteins or the clone cDNAs encoding proteins that bind the cytoplasmic tail recently developed cDNA cloning system that uses yeast of CD40. A cDNA encoding a putative signal transducer genetic selection led to the discovery of two groups of signal protein, designated TRAF5, has been molecularly cloned. transducer molecules. Members of the first group are proteins TRAF5 has a tumor necrosis factor receptor-associated factor with a TRAF domain for TNFR2 and CD40 such as TRAF1, (TRAF) domain in its carboxyl terminus and is most homol- TRAF2 (17), and TRAF3, also known as CD40bp, LAP-1, or ogous to TRAF3, also known as CRAF1, CD40bp, or LAP-1, CRAF1 or CD40 receptor-associated factor (18-20).
    [Show full text]
  • Differential Gene Expression in Oligodendrocyte Progenitor Cells, Oligodendrocytes and Type II Astrocytes
    Tohoku J. Exp. Med., 2011,Differential 223, 161-176 Gene Expression in OPCs, Oligodendrocytes and Type II Astrocytes 161 Differential Gene Expression in Oligodendrocyte Progenitor Cells, Oligodendrocytes and Type II Astrocytes Jian-Guo Hu,1,2,* Yan-Xia Wang,3,* Jian-Sheng Zhou,2 Chang-Jie Chen,4 Feng-Chao Wang,1 Xing-Wu Li1 and He-Zuo Lü1,2 1Department of Clinical Laboratory Science, The First Affiliated Hospital of Bengbu Medical College, Bengbu, P.R. China 2Anhui Key Laboratory of Tissue Transplantation, Bengbu Medical College, Bengbu, P.R. China 3Department of Neurobiology, Shanghai Jiaotong University School of Medicine, Shanghai, P.R. China 4Department of Laboratory Medicine, Bengbu Medical College, Bengbu, P.R. China Oligodendrocyte precursor cells (OPCs) are bipotential progenitor cells that can differentiate into myelin-forming oligodendrocytes or functionally undetermined type II astrocytes. Transplantation of OPCs is an attractive therapy for demyelinating diseases. However, due to their bipotential differentiation potential, the majority of OPCs differentiate into astrocytes at transplanted sites. It is therefore important to understand the molecular mechanisms that regulate the transition from OPCs to oligodendrocytes or astrocytes. In this study, we isolated OPCs from the spinal cords of rat embryos (16 days old) and induced them to differentiate into oligodendrocytes or type II astrocytes in the absence or presence of 10% fetal bovine serum, respectively. RNAs were extracted from each cell population and hybridized to GeneChip with 28,700 rat genes. Using the criterion of fold change > 4 in the expression level, we identified 83 genes that were up-regulated and 89 genes that were down-regulated in oligodendrocytes, and 92 genes that were up-regulated and 86 that were down-regulated in type II astrocytes compared with OPCs.
    [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]
  • Crystallographic Analysis of CD40 Recognition and Signaling by Human TRAF2
    Proc. Natl. Acad. Sci. USA Vol. 96, pp. 8408–8413, July 1999 Biochemistry Crystallographic analysis of CD40 recognition and signaling by human TRAF2 SARAH M. MCWHIRTER*, STEVEN S. PULLEN†,JAMES M. HOLTON*, JAMES J. CRUTE†,MARILYN R. KEHRY†, AND TOM ALBER*‡ *Department of Molecular and Cell Biology, University of California, Berkeley, CA 94720-3206, and †Boehringer Ingelheim Pharmaceuticals, Inc., Ridgefield, CT 06877-0368 Communicated by Peter S. Kim, Massachusetts Institute of Technology, Cambridge, MA, May 26, 1999 (received for review April 25, 1999) ABSTRACT Tumor necrosis factor receptor superfamily proteins (8, 9). The biological selectivity of signaling also relies members convey signals that promote diverse cellular re- on the oligomerization specificity and receptor affinity of the sponses. Receptor trimerization by extracellular ligands ini- TRAFs. tiates signaling by recruiting members of the tumor necrosis The TNF receptor superfamily member, CD40, mediates factor receptor-associated factor (TRAF) family of adapter diverse responses. In antigen-presenting cells that constitu- proteins to the receptor cytoplasmic domains. We report the tively express CD40, it plays a critical role in T cell-dependent 2.4-Å crystal structure of a 22-kDa, receptor-binding fragment immune responses (10). TRAF1, TRAF2, TRAF3, and of TRAF2 complexed with a functionally defined peptide from TRAF6 binding sites in the 62-aa, CD40 cytoplasmic domain the cytoplasmic domain of the CD40 receptor. TRAF2 forms have been mapped (7, 11). TRAF1, TRAF2, and TRAF3 bind a mushroom-shaped trimer consisting of a coiled coil and a to the same sequence, 250PVQET, and TRAF6 binds to the unique ␤-sandwich domain. Both domains mediate trimer- membrane-proximal sequence, 231QEPQEINF.
    [Show full text]
  • Molecular Signatures Differentiate Immune States in Type 1 Diabetes Families
    Page 1 of 65 Diabetes Molecular signatures differentiate immune states in Type 1 diabetes families Yi-Guang Chen1, Susanne M. Cabrera1, Shuang Jia1, Mary L. Kaldunski1, Joanna Kramer1, Sami Cheong2, Rhonda Geoffrey1, Mark F. Roethle1, Jeffrey E. Woodliff3, Carla J. Greenbaum4, Xujing Wang5, and Martin J. Hessner1 1The Max McGee National Research Center for Juvenile Diabetes, Children's Research Institute of Children's Hospital of Wisconsin, and Department of Pediatrics at the Medical College of Wisconsin Milwaukee, WI 53226, USA. 2The Department of Mathematical Sciences, University of Wisconsin-Milwaukee, Milwaukee, WI 53211, USA. 3Flow Cytometry & Cell Separation Facility, Bindley Bioscience Center, Purdue University, West Lafayette, IN 47907, USA. 4Diabetes Research Program, Benaroya Research Institute, Seattle, WA, 98101, USA. 5Systems Biology Center, the National Heart, Lung, and Blood Institute, the National Institutes of Health, Bethesda, MD 20824, USA. Corresponding author: Martin J. Hessner, Ph.D., The Department of Pediatrics, The Medical College of Wisconsin, Milwaukee, WI 53226, USA Tel: 011-1-414-955-4496; Fax: 011-1-414-955-6663; E-mail: [email protected]. Running title: Innate Inflammation in T1D Families Word count: 3999 Number of Tables: 1 Number of Figures: 7 1 For Peer Review Only Diabetes Publish Ahead of Print, published online April 23, 2014 Diabetes Page 2 of 65 ABSTRACT Mechanisms associated with Type 1 diabetes (T1D) development remain incompletely defined. Employing a sensitive array-based bioassay where patient plasma is used to induce transcriptional responses in healthy leukocytes, we previously reported disease-specific, partially IL-1 dependent, signatures associated with pre and recent onset (RO) T1D relative to unrelated healthy controls (uHC).
    [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]
  • Family in Amphioxus, the Basal Chordate TNF Receptor-Associated
    Genomic and Functional Uniqueness of the TNF Receptor-Associated Factor Gene Family in Amphioxus, the Basal Chordate This information is current as Shaochun Yuan, Tong Liu, Shengfeng Huang, Tao Wu, Ling of September 26, 2021. Huang, Huiling Liu, Xin Tao, Manyi Yang, Kui Wu, Yanhong Yu, Meiling Dong and Anlong Xu J Immunol 2009; 183:4560-4568; Prepublished online 14 September 2009; doi: 10.4049/jimmunol.0901537 Downloaded from http://www.jimmunol.org/content/183/7/4560 Supplementary http://www.jimmunol.org/content/suppl/2009/09/14/jimmunol.090153 Material 7.DC1 http://www.jimmunol.org/ References This article cites 38 articles, 12 of which you can access for free at: http://www.jimmunol.org/content/183/7/4560.full#ref-list-1 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision by guest on September 26, 2021 • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2009 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Genomic and Functional Uniqueness of the TNF Receptor-Associated Factor Gene Family in Amphioxus, the Basal Chordate1 Shaochun Yuan, Tong Liu, Shengfeng Huang, Tao Wu, Ling Huang, Huiling Liu, Xin Tao, Manyi Yang, Kui Wu, Yanhong Yu, Meiling Dong, and Anlong Xu2 The TNF-associated factor (TRAF) family, the crucial adaptor group in innate immune signaling, increased to 24 in amphioxus, the oldest lineage of the Chordata.
    [Show full text]
  • Grouper TRAF4, a Novel, CP-Interacting Protein That Promotes Red-Spotted Grouper Nervous Necrosis Virus Replication
    International Journal of Molecular Sciences Article Grouper TRAF4, a Novel, CP-Interacting Protein That Promotes Red-Spotted Grouper Nervous Necrosis Virus Replication Siting Wu 1, Mengshi Sun 1, Xin Zhang 1, Jiaming Liao 1, Mengke Liu 1, Qiwei Qin 1,2,* and Jingguang Wei 1,* 1 Guangdong Laboratory for Lingnan Modern Agriculture, Joint Laboratory of Guangdong Province and Hong Kong Region on Marine Bioresource Conservation and Exploitation, College of Marine Sciences, South China Agricultural University, Guangzhou 510642, China; [email protected] (S.W.); [email protected] (M.S.); [email protected] (X.Z.); [email protected] (J.L.); [email protected] (M.L.) 2 Laboratory for Marine Biology and Biotechnology, Qingdao National Laboratory for Marine Science and Technology, Qingdao 266000, China * Correspondence: [email protected] (Q.Q.); [email protected] (J.W.) Abstract: Tumor necrosis factor receptor-associated factors (TRAFs) play important roles in the biological processes of immune regulation, the inflammatory response, and apoptosis. TRAF4 belongs to the TRAF family and plays a major role in many biological processes. Compared with other TRAF proteins, the functions of TRAF4 in teleosts have been largely unknown. In the present study, the TRAF4 homologue (EcTRAF4) of the orange-spotted grouper was characterized. EcTRAF4 consisted of 1413 bp encoding a 471-amino-acid protein, and the predicted molecular mass was 54.27 kDa. EcTRAF4 shares 99.79% of its identity with TRAF4 of the giant grouper (E. lanceolatus). EcTRAF4 transcripts were ubiquitously and differentially expressed in all the examined tissues. EcTRAF4 Citation: Wu, S.; Sun, M.; Zhang, X.; expression in GS cells was significantly upregulated after stimulation with red-spotted grouper Liao, J.; Liu, M.; Qin, Q.; Wei, J.
    [Show full text]