76 results found
Chairakaki A-D, Saridaki M-I, Pyrillou K, et al., 2018, Plasmacytoid dendritic cells drive acute exacerbations of asthma, Journal of Allergy and Clinical Immunology, Vol: 142, Pages: 542-556.e12, ISSN: 0091-6749
BACKGROUND: Although acute exacerbations, mostly triggered by viruses, account for the majority of hospitalizations in asthma, there is still very little known about the pathophysiological mechanisms involved. Plasmacytoid DCs (pDCs), prominent cells of antiviral immunity, exhibit pro-inflammatory or tolerogenic functions depending on the context, yet their involvement in asthma exacerbations remains unexplored. OBJECTIVES: We sought to investigate the role of pDCs in allergic airway inflammation and acute exacerbations of asthma. METHODS: Animal models of allergic airway disease (AAD) and virus-induced AAD exacerbations were employed to dissect pDC function in vivo and unwind potential mechanisms involved. Sputum from asthma patients with stable disease or acute exacerbations was further studied to determine pDC presence and correlation with inflammation. RESULTS: pDCs were key mediators of the immuno-inflammatory cascade that drives asthma exacerbations. In animal models of AAD and RV-induced AAD exacerbations, pDCs were recruited to the lung during inflammation and migrated to the draining lymph nodes to boost Th2-mediated effector responses. Accordingly, pDC depletion post-allergen challenge or during RV infection abrogated exacerbation of inflammation and disease. Central to this process was IL-25, induced by allergen challenge or RV infection that conditioned pDCs for pro-inflammatory function. Consistently, in asthma patients pDCs were markedly increased during exacerbations, and correlated with the severity of inflammation and the risk for asthmatic attacks. CONCLUSIONS: Our studies uncover a previously unsuspected role of pDCs in asthma exacerbations with potential diagnostic and prognostic implications. They also propose the therapeutic targeting of pDCs and IL-25 for the treatment of acute asthma.
Reid AT, Veerati PC, Gosens R, et al., 2018, Persistent induction of goblet cell differentiation in the airways: Therapeutic approaches, PHARMACOLOGY & THERAPEUTICS, Vol: 185, Pages: 155-169, ISSN: 0163-7258
Asthma remains the most prevalent chronic respiratory disorder, affecting people of all ages. The relationship between respiratory virus infection and asthma has long been recognized, though remains incompletely understood. In this article, we will address key issues around this relationship. These will include the crucial role virus infection plays in early life, as a potential risk factor for the development of asthma and lung disease. We will assess the impact that virus infection has on those with established asthma as a trigger for acute disease and how this may influence asthma throughout life. Finally, we will explore the complex interaction that occurs between the airway and the immune responses that make those with asthma so susceptible to the effects of virus infection.
Toussaint M, Jackson DJ, Swieboda D, et al., 2017, Host DNA released by NETosis promotes rhinovirus-induced type-2 allergic asthma exacerbation, Nature Medicine, Vol: 23, Pages: 681-691, ISSN: 1078-8956
Respiratory viral infections represent the most common cause of allergic asthma exacerbations. Amplification of the type-2 immune response is strongly implicated in asthma exacerbation, but how virus infection boosts type-2 responses is poorly understood. We report a significant correlation between the release of host double-stranded DNA (dsDNA) following rhinovirus infection and the exacerbation of type-2 allergic inflammation in humans. In a mouse model of allergic airway hypersensitivity, we show that rhinovirus infection triggers dsDNA release associated with the formation of neutrophil extracellular traps (NETs), known as NETosis. We further demonstrate that inhibiting NETosis by blocking neutrophil elastase or by degrading NETs with DNase protects mice from type-2 immunopathology. Furthermore, the injection of mouse genomic DNA alone is sufficient to recapitulate many features of rhinovirus-induced type-2 immune responses and asthma pathology. Thus, NETosis and its associated extracellular dsDNA contribute to the pathogenesis and may represent potential therapeutic targets of rhinovirus-induced asthma exacerbations.
Tunstall T, Kon OM, Bartlett N, et al., 2017, A Comprehensive Evaluation of Nasal and Bronchial Cytokines and Chemokines Following Experimental Rhinovirus Infection in Allergic Asthma: Increased Interferons (IFN-γ and IFN-λ) and Type 2 Inflammation (IL-5 and IL-13), EBioMedicine, Vol: 19, Pages: 128-138, ISSN: 2352-3964
BackgroundRhinovirus infection is a major cause of asthma exacerbations.ObjectivesWe studied nasal and bronchial mucosal inflammatory responses during experimental rhinovirus-induced asthma exacerbations.MethodsWe used nasosorption on days 0, 2–5 and 7 and bronchosorption at baseline and day 4 to sample mucosal lining fluid to investigate airway mucosal responses to rhinovirus infection in patients with allergic asthma (n = 28) and healthy non-atopic controls (n = 11), by using a synthetic absorptive matrix and measuring levels of 34 cytokines and chemokines using a sensitive multiplex assay.ResultsFollowing rhinovirus infection asthmatics developed more upper and lower respiratory symptoms and lower peak expiratory flows compared to controls (all P < 0.05). Asthmatics also developed higher nasal lining fluid levels of an anti-viral pathway (including IFN-γ, IFN-λ/IL-29, CXCL11/ITAC, CXCL10/IP10 and IL-15) and a type 2 inflammatory pathway (IL-4, IL-5, IL-13, CCL17/TARC, CCL11/eotaxin, CCL26/eotaxin-3) (area under curve day 0–7, all P < 0.05). Nasal IL-5 and IL-13 were higher in asthmatics at day 0 (P < 0.01) and levels increased by days 3 and 4 (P < 0.01). A hierarchical correlation matrix of 24 nasal lining fluid cytokine and chemokine levels over 7 days demonstrated expression of distinct interferon-related and type 2 pathways in asthmatics. In asthmatics IFN-γ, CXCL10/IP10, CXCL11/ITAC, IL-15 and IL-5 increased in bronchial lining fluid following viral infection (all P < 0.05).ConclusionsPrecision sampling of mucosal lining fluid identifies robust interferon and type 2 responses in the upper and lower airways of asthmatics during an asthma exacerbation. Nasosorption and bronchosorption have potential to define asthma endotypes in stable disease and at exacerbation.
Petrova NV, Emelyanova AG, Gorbunov EA, et al., 2017, Efficacy of novel antibody-based drugs against rhinovirus infection: In vitro and in vivo results, ANTIVIRAL RESEARCH, Vol: 142, Pages: 185-192, ISSN: 0166-3542
Tay H, Wark PAB, Bartlett NW, 2016, Advances in the treatment of virus-induced asthma, Expert Review of Respiratory Medicine, Vol: 10, Pages: 629-641, ISSN: 1747-6348
Viral exacerbations continue to represent the major burden in terms of morbidity, mortality and health care costs associated with asthma. Those at greatest risk for acute asthma are those with more severe airways disease and poor asthma control. It is this group with established asthma in whom acute exacerbations triggered by virus infections remain a serious cause of increased morbidity. A range of novel therapies are emerging to treat asthma and in particular target this group with poor disease control, and in most cases their efficacy is now being judged by their ability to reduce the frequency of acute exacerbations. Critical for the development of new treatment approaches is an improved understanding of virus-host interaction in the context of the asthmatic airway. This requires research into the virology of the disease in physiological models in conjunction with detailed phenotypic characterisation of asthma patients to identify targets amenable to therapeutic intervention.
Bartlett N, Singanayagam A, Johnston S, 2016, INHALED CORTICOSTEROIDS SUPPRESS INNATE AND ADAPTIVE ANTI-VIRAL IMMUNE RESPONSES IN THE AIRWAYS, RESPIROLOGY, Vol: 21, Pages: 34-34, ISSN: 1323-7799
Singanayagam A, Glanville N, Pearson R, et al., 2015, FLUTICASONE PROPIONATE ALTERS THE RESIDENT AIRWAY MICROBIOTA AND IMPAIRS ANTI-VIRAL AND ANTI-BACTERIAL IMMUNE RESPONSES IN THE AIRWAYS, Winter Meeting of the British-Thoracic-Society, Publisher: BMJ PUBLISHING GROUP, Pages: A1-A1, ISSN: 0040-6376
Hatchwell L, Collison A, Girkin J, et al., 2015, Toll-like receptor 7 governs interferon and inflammatory responses to rhinovirus and is suppressed by IL-5-induced lung eosinophilia, Thorax, Vol: 70, Pages: 854-861, ISSN: 0040-6376
Background Asthma exacerbations represent asignificant disease burden and are commonly caused byrhinovirus (RV), which is sensed by Toll-like receptors(TLR) such as TLR7. Some asthmatics have impairedinterferon (IFN) responses to RV, but the underlyingmechanisms of this clinically relevant observation arepoorly understood.Objectives To investigate the importance of intactTLR7 signalling in vivo during RV exacerbation usingmouse models of house dust mite (HDM)-inducedallergic airways disease exacerbated by a superimposedRV infection.Methods Wild-type and TLR7-deficient (Tlr7−/−) BALB/c mice were intranasally sensitised and challenged withHDM prior to infection with RV1B. In some experiments,mice were administered recombinant IFN or adoptivelytransferred with plasmacytoid dendritic cells (pDC).Results Allergic Tlr7−/− mice displayed impaired IFNrelease upon RV1B infection, increased virus replicationand exaggerated eosinophilic inflammation and airwayshyper reactivity. Treatment with exogenous IFN oradoptive transfer of TLR7-competent pDCs blocked theseexaggerated inflammatory responses and boosted IFNγrelease in the absence of host TLR7 signalling. TLR7expression in the lungs was suppressed by allergicinflammation and by interleukin (IL)-5-inducedeosinophilia in the absence of allergy. Subjects withmoderate-to-severe asthma and eosinophilic but notneutrophilic airways inflammation, despite inhaledsteroids, showed reduced TLR7 and IFNλ2/3 expressionin endobronchial biopsies. Furthermore, TLR7 expressioninversely correlated with percentage of sputumeosinophils.Conclusions This implicates IL-5-induced airwayseosinophilia as a negative regulator of TLR7 expressionand antiviral responses, which provides a molecularmechanism underpinning the effect of eosinophiltargetingtreatments for the prevention of asthmaexacerbations.
Singanayagam A, Glanville N, Walton RP, et al., 2015, A short-term mouse model that reproduces the immunopathological features of rhinovirus-induced exacerbation of COPD, Clinical Science, Vol: 129, Pages: 245-258, ISSN: 1470-8736
Viral exacerbations of chronic obstructive pulmonary disease (COPD), commonly caused by rhinovirus (RV) infections, are poorly controlled by current therapies. This is due to a lack of understanding of the underlying immunopathological mechanisms. Human studies have identified a number of key immune responses that are associated with RV-induced exacerbations including neutrophilic inflammation, expression of inflammatory cytokines and deficiencies in innate anti-viral interferon. Animal models of COPD exacerbation are required to determine the contribution of these responses to disease pathogenesis. We aimed to develop a short-term mouse model that reproduced the hallmark features of RV-induced exacerbation of COPD. Evaluation of complex protocols involving multiple dose elastase and lipopolysaccharide (LPS) administration combined with RV1B infection showed suppression rather than enhancement of inflammatory parameters compared with control mice infected with RV1B alone. Therefore, these approaches did not accurately model the enhanced inflammation associated with RV infection in patients with COPD compared with healthy subjects. In contrast, a single elastase treatment followed by RV infection led to heightened airway neutrophilic and lymphocytic inflammation, increased expression of tumour necrosis factor (TNF)-α, C-X-C motif chemokine 10 (CXCL10)/IP-10 (interferon γ-induced protein 10) and CCL5 [chemokine (C-C motif) ligand 5]/RANTES (regulated on activation, normal T-cell expressed and secreted), mucus hypersecretion and preliminary evidence for increased airway hyper-responsiveness compared with mice treated with elastase or RV infection alone. In summary, we have developed a new mouse model of RV-induced COPD exacerbation that mimics many of the inflammatory features of human disease. This model, in conjunction with human models of disease, will provide an essential tool for studying disease mechanisms and allow testing of novel therapies with pot
Jackson DJ, Trujillo-Torralbo M-B, del-Rosario J, et al., 2015, The influence of asthma control on the severity of virus-induced asthma exacerbations, Journal of Allergy and Clinical Immunology, Vol: 136, Pages: 497-500.e3, ISSN: 1097-6825
Girkin J, Hatchwell L, Foster P, et al., 2015, CCL7 and IRF-7 Mediate Hallmark Inflammatory and IFN Responses following Rhinovirus 1B Infection, Journal of Immunology, Vol: 194, Pages: 4924-4930, ISSN: 1550-6606
Rhinovirus (RV) infections are common and have the potential to exacerbate asthma. We have determined the lung transcriptome in RV strain 1B–infected naive BALB/c mice (nonallergic) and identified CCL7 and IFN regulatory factor (IRF)-7 among the most upregulated mRNA transcripts in the lung. To investigate their roles we employed anti-CCL7 Abs and an IRF-7–targeting small interfering RNA in vivo. Neutralizing CCL7 or inhibiting IRF-7 limited neutrophil and macrophage influx and IFN responses in nonallergic mice. Neutralizing CCL7 also reduced activation of NF-κB p65 and p50 subunits, as well as airway hyperreactivity (AHR) in nonallergic mice. However, neither NF-κB subunit activation nor AHR was abolished with infection of allergic mice after neutralizing CCL7, despite a reduction in the number of neutrophils, macrophages, and eosinophils. IRF-7 small interfering RNA primarily suppressed IFN-α and IFN-β levels during infection of allergic mice. Our data highlight a pivotal role of CCL7 and IRF-7 in RV-induced inflammation and IFN responses and link NF-κB signaling to the development of AHR.
Singanayagam A, Glanville N, Bartlett N, et al., 2015, Effect of fluticasone propionate on virus-induced airways inflammation and anti-viral immune responses in mice, Spring Meeting on Clinician Scientists in Training, Publisher: ELSEVIER SCIENCE INC, Pages: 88-88, ISSN: 0140-6736
Bartlett NW, Singanayagam A, Johnston SL, 2015, Mouse models of rhinovirus infection and airways disease., Methods Mol Biol, Vol: 1221, Pages: 181-188
Mouse models are invaluable tools for gaining insight into host immunity during virus infection. Until recently, no practical mouse model for rhinovirus infection was available. Development of infection models was complicated by the existence of distinct groups of viruses that utilize different host cell surface proteins for binding and entry. Here, we describe mouse infection models, including virus purification and measurement of host immune responses, for representative viruses from two of these groups: (1) infection of unmodified Balb/c mice with minor group rhinovirus serotype 1B (RV-1B) and (2) infection of transgenic Balb/c mice with major group rhinovirus serotype 16 (RV-16).
Jackson DJ, Makrinioti H, Rana BMJ, et al., 2014, IL-33-dependent Type 2 inflammation during rhinovirus-induced asthma exacerbations in vivo, American Journal of Respiratory and Critical Care Medicine, Vol: 190, Pages: 1373-1382, ISSN: 1535-4970
Rationale: Rhinoviruses are the major cause of asthmaexacerbations; however, its underlying mechanisms are poorlyunderstood. We hypothesized that the epithelial cell–derivedcytokine IL-33 plays a central role in exacerbation pathogenesisthrough augmentation of type 2 inflammation.Objectives: To assess whether rhinovirus induces a type 2inflammatory response in asthma in vivo and to define a role for IL-33in this pathway.Methods: We used a human experimental model of rhinovirusinfection and novel airway sampling techniques to measure IL-4, IL-5,IL-13, and IL-33 levels in the asthmatic and healthy airways duringa rhinovirus infection. Additionally, we cultured human T cells and type2 innate lymphoid cells (ILC2s) with the supernatants of rhinovirusinfectedbronchial epithelial cells (BECs) to assess type 2 cytokineproduction in the presence or absence of IL-33 receptor blockade.Measurements and Main Results: IL-4, IL-5, IL-13, and IL-33 areall induced by rhinovirus in the asthmatic airway in vivo and relate toexacerbation severity. Further, induction of IL-33 correlates withviral load and IL-5 and IL-13 levels. Rhinovirus infection of humanprimary BECs induced IL-33, and culture of human T cells and ILC2swith supernatants of rhinovirus-infected BECs strongly inducedtype 2 cytokines. This induction was entirely dependent on IL-33.Conclusions: IL-33 and type 2 cytokines are induced duringa rhinovirus-induced asthma exacerbation in vivo. Virus-inducedIL-33 and IL-33–responsive T cells and ILC2s are key mechanisticlinks between viral infection and exacerbation of asthma. IL-33inhibition is a novel therapeutic approach for asthma exacerbations
Beale J, Jayaraman A, Jackson DJ, et al., 2014, Rhinovirus-induced IL-25 in asthma exacerbation drives type 2 immunity and allergic pulmonary inflammation, Science Translational Medicine, Vol: 6, ISSN: 1946-6234
Rhinoviruses (RVs), which are the most common cause of virally induced asthma exacerbations, account for much of the burden of asthma in terms of morbidity, mortality, and associated cost. Interleukin-25 (IL-25) activates type 2–driven inflammation and is therefore potentially important in virally induced asthma exacerbations. To investigate this, we examined whether RV-induced IL-25 could contribute to asthma exacerbations. RV-infected cultured asthmatic bronchial epithelial cells exhibited a heightened intrinsic capacity for IL-25 expression, which correlated with donor atopic status. In vivo human IL-25 expression was greater in asthmatics at baseline and during experimental RV infection. In addition, in mice, RV infection induced IL-25 expression and augmented allergen-induced IL-25. Blockade of the IL-25 receptor reduced many RV-induced exacerbation-specific responses including type 2 cytokine expression, mucus production, and recruitment of eosinophils, neutrophils, basophils, and T and non-T type 2 cells. Therefore, asthmatic epithelial cells have an increased intrinsic capacity for expression of a pro–type 2 cytokine in response to a viral infection, and IL-25 is a key mediator of RV-induced exacerbations of pulmonary inflammation.
Jayaraman A, Jackson DJ, Message SD, et al., 2014, IL-15 complexes induce NK- and T-cell responses independent of type I IFN signaling during rhinovirus infection, MUCOSAL IMMUNOLOGY, Vol: 7, Pages: 1151-1164, ISSN: 1933-0219
Rhinoviruses are among the most common viruses to infect man, causing a range of serious respiratory diseases including exacerbations of asthma and COPD. Type I IFN and IL-15 are thought to be required for antiviral immunity; however, their function during rhinovirus infection in vivo is undefined. In RV-infected human volunteers, IL-15 protein expression in fluid from the nasal mucosa and in bronchial biopsies was increased. In mice, RV induced type I IFN-dependent expressions of IL-15 and IL-15Rα, which in turn were required for NK- and CD8+ T-cell responses. Treatment with IL-15–IL-15Rα complexes (IL-15c) boosted RV-induced expression of IL-15, IL-15Rα, IFN-γ, CXCL9, and CXCL10 followed by recruitment of activated, IFN-γ-expressing NK, CD8+, and CD4+ T cells. Treating infected IFNAR1−/− mice with IL-15c similarly increased IL-15, IL-15Rα, IFN-γ, and CXCL9 (but not CXCL10) expression also followed by NK-, CD8+-, and CD4+-T-cell recruitment and activation. We have demonstrated that type I IFN-induced IFN-γ and cellular immunity to RV was mediated by IL-15 and IL-15Rα. Importantly, we also show that IL-15 could be induced via a type I IFN-independent mechanism by IL-15 complex treatment, which in turn was sufficient to drive IFN-γ expression and lymphocyte responses.
Toussaint M, Singanayagam A, Bartlett N, et al., 2014, Rhinovirus increases allergen-induced IL-33 and exacerbates type-2 immunity and pulmonary inflammation, European-Academy-of-Allergy-and-Clinical-Immunology Congress, Publisher: WILEY-BLACKWELL, Pages: 601-601, ISSN: 0105-4538
Collison A, Hatchwell L, Girkin J, et al., 2014, REDUCED TLR7 EXPRESSION MAY UNDERPIN IMPAIRED RESPONSE TO VIRAL INFECTION IN ASTHMA, RESPIROLOGY, Vol: 19, Pages: 14-14, ISSN: 1323-7799
Mahmutovic-Persson I, Akbarshahi H, Bartlett NW, et al., 2014, Inhaled dsRNA and rhinovirus evoke neutrophilic exacerbation and lung expression of thymic stromal lymphopoietin in allergic mice with established experimental asthma, ALLERGY, Vol: 69, Pages: 348-358, ISSN: 0105-4538
George PM, Oliver E, Dorfmuller P, et al., 2014, Evidence for the Involvement of Type I Interferon in Pulmonary Arterial Hypertension, CIRCULATION RESEARCH, Vol: 114, Pages: 677-688, ISSN: 0009-7330
Jayaraman A, Bartlett N, Johnston SL, 2014, Innate and Adaptive Lymphocyte Responses In a Mouse Model Of Rhinovirus-Induced Asthma Exacerbation, Annual Meeting of the American-Academy-of-Allergy-Asthma-and-Immunology (AAAAI), Publisher: MOSBY-ELSEVIER, Pages: AB135-AB135, ISSN: 0091-6749
Toussaint M, Singanayagam A, Johnston SL, et al., 2014, Role Of Interleukine-33 In Rhinovirus-Induced Allergic Asthma Exacerbation, Annual Meeting of the American-Academy-of-Allergy-Asthma-and-Immunology (AAAAI), Publisher: MOSBY-ELSEVIER, Pages: AB52-AB52, ISSN: 0091-6749
Ching Y-M, Edwards MR, Glanville N, et al., 2014, Innate Type I Interferon Signalling Modulates Th2 Responses In Mouse Models Of Rhinovirus-Induced Airways Disease, AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, Vol: 189, ISSN: 1073-449X
Jackson DJ, Shamji B, Trujillo-Torralbo M-B, et al., 2014, Prostaglandin D2 Is Induced During Rhinovirus-Induced Asthma Exacerbations And Related To Exacerbation Severity In Vivo, AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, Vol: 189, ISSN: 1073-449X
Brignull LM, Czimmerer Z, Saidi H, et al., 2013, Reprogramming of lysosomal gene expression by interleukin-4 and Stat6, BMC Genomics, Vol: 14, ISSN: 1471-2164
BackgroundLysosomes play important roles in multiple aspects of physiology, but the problem of how the transcription of lysosomal genes is coordinated remains incompletely understood. The goal of this study was to illuminate the physiological contexts in which lysosomal genes are coordinately regulated and to identify transcription factors involved in this control.ResultsAs transcription factors and their target genes are often co-regulated, we performed meta-analyses of array-based expression data to identify regulators whose mRNA profiles are highly correlated with those of a core set of lysosomal genes. Among the ~50 transcription factors that rank highest by this measure, 65% are involved in differentiation or development, and 22% have been implicated in interferon signaling. The most strongly correlated candidate was Stat6, a factor commonly activated by interleukin-4 (IL-4) or IL-13. Publicly available chromatin immunoprecipitation (ChIP) data from alternatively activated mouse macrophages show that lysosomal genes are overrepresented among Stat6-bound targets. Quantification of RNA from wild-type and Stat6-deficient cells indicates that Stat6 promotes the expression of over 100 lysosomal genes, including hydrolases, subunits of the vacuolar H+ ATPase and trafficking factors. While IL-4 inhibits and activates different sets of lysosomal genes, Stat6 mediates only the activating effects of IL-4, by promoting increased expression and by neutralizing undefined inhibitory signals induced by IL-4.ConclusionsThe current data establish Stat6 as a broadly acting regulator of lysosomal gene expression in mouse macrophages. Other regulators whose expression correlates with lysosomal genes suggest that lysosome function is frequently re-programmed during differentiation, development and interferon signaling.
McLean G, Glanville N, Guy B, et al., 2013, Immunization with a conserved rhinovirus capsid protein generates cross-serotype protective immune responses, Annual Congress of the British-Society-for-Immunology, Publisher: WILEY-BLACKWELL, Pages: 39-39, ISSN: 0019-2805
George PM, Oliver E, Schreiber BE, et al., 2013, EVIDENCE THAT TYPE I INTERFERON DRIVES PULMONARY ARTERIAL HYPERTENSION, Winter Meeting of the British-Thoracic-Society, Publisher: BMJ PUBLISHING GROUP, Pages: A73-A74, ISSN: 0040-6376
Glanville N, Message SD, Walton RP, et al., 2013, γδT cells suppress inflammation and disease during rhinovirus-induced asthma exacerbations, Mucosal Immunology, Vol: 6, Pages: 1091-1100, ISSN: 1933-0219
Most asthma exacerbations are triggered by virus infections, the majority being caused by human rhinoviruses (RV). In mouse models, γδT cells have been previously demonstrated to influence allergen-driven airways hyper-reactivity (AHR) and can have antiviral activity, implicating them as prime candidates in the pathogenesis of asthma exacerbations. To explore this, we have used human and mouse models of experimental RV-induced asthma exacerbations to examine γδT-cell responses and determine their role in the immune response and associated airways disease. In humans, airway γδT-cell numbers were increased in asthmatic vs. healthy control subjects during experimental infection. Airway and blood γδT-cell numbers were associated with increased airways obstruction and AHR. Airway γδT-cell number was also positively correlated with bronchoalveolar lavage (BAL) virus load and BAL eosinophils and lymphocytes during RV infection. Consistent with our observations of RV-induced asthma exacerbations in humans, infection of mice with allergic airways inflammation increased lung γδT-cell number and activation. Inhibiting γδT-cell responses using anti-γδTCR (anti-γδT-cell receptor) antibody treatment in the mouse asthma exacerbation model increased AHR and airway T helper type 2 cell recruitment and eosinophilia, providing evidence that γδT cells are negative regulators of airways inflammation and disease in RV-induced asthma exacerbations.
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