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- Al-Garawi, A., et al.
(författare)
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Influenza A facilitates sensitization to house dust mite in infant mice leading to an asthma phenotype in adulthood
- 2011
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Ingår i: Mucosal Immunology. - : Elsevier BV. - 1933-0219. ; 4:6, s. 682-694
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Tidskriftsartikel (refereegranskat)abstract
- The origins of allergic asthma, particularly in infancy, remain obscure. Respiratory viral infections and allergen sensitization in early life have been associated with asthma in young children. However, a causal link has not been established. We investigated whether an influenza A infection in early life alters immune responses to house dust mite (HDM) and promotes an asthmatic phenotype later in life. Neonatal (8-day-old) mice were infected with influenza virus and 7 days later, exposed to HDM for 3 weeks. Unlike adults, neonatal mice exposed to HDM exhibited negligible immune responsiveness to HDM, but not to influenza A. HDM responsiveness in adults was associated with distinct Ly6c(+) CD11b(+) inflammatory dendritic cell and CD8 alpha(+) plasmacytoid (pDC) populations that were absent in HDM-exposed infant mice, suggesting an important role in HDM-mediated inflammation. Remarkably, HDM hyporesponsiveness was overcome when exposure occurred concurrently with an acute influenza infection; young mice now displayed robust allergen-specific immunity, allergic inflammation, and lung remodeling. Remodeling persisted into early adulthood, even after prolonged discontinuation of allergen exposure and was associated with marked impairment of lung function. Our data demonstrate that allergen exposure coincident with acute viral infection in early life subverts constitutive allergen hyporesponsiveness and imprints an asthmatic phenotype in adulthood.
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- Chu, Derek K, et al.
(författare)
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Indigenous enteric eosinophils control DCs to initiate a primary Th2 immune response in vivo.
- 2014
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Ingår i: Journal of Experimental Medicine. - : Rockefeller University Press. - 1540-9538 .- 0022-1007. ; 211:8, s. 1657-1672
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Tidskriftsartikel (refereegranskat)abstract
- Eosinophils natively inhabit the small intestine, but a functional role for them there has remained elusive. Here, we show that eosinophil-deficient mice were protected from induction of Th2-mediated peanut food allergy and anaphylaxis, and Th2 priming was restored by reconstitution with il4(+/+) or il4(-/-) eosinophils. Eosinophils controlled CD103(+) dendritic cell (DC) activation and migration from the intestine to draining lymph nodes, events necessary for Th2 priming. Eosinophil activation in vitro and in vivo led to degranulation of eosinophil peroxidase, a granule protein whose enzymatic activity promoted DC activation in mice and humans in vitro, and intestinal and extraintestinal mouse DC activation and mobilization to lymph nodes in vivo. Further, eosinophil peroxidase enhanced responses to ovalbumin seen after immunization. Thus, eosinophils can be critical contributors to the intestinal immune system, and granule-mediated shaping of DC responses can promote both intestinal and extraintestinal adaptive immunity.
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- Kearley, Jennifer, et al.
(författare)
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Cigarette smoke silences innate lymphoid cell function and facilitates an exacerbated type I interleukin-33-dependent response to infection.
- 2015
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Ingår i: Immunity. - : Elsevier BV. - 1074-7613. ; 42:3, s. 566-579
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Tidskriftsartikel (refereegranskat)abstract
- Cigarette smoking is a major risk factor for chronic obstructive pulmonary disease and is presumed to be central to the altered responsiveness to recurrent infection in these patients. We examined the effects of smoke priming underlying the exacerbated response to viral infection in mice. Lack of interleukin-33 (IL-33) signaling conferred complete protection during exacerbation and prevented enhanced inflammation and exaggerated weight loss. Mechanistically, smoke was required to upregulate epithelial-derived IL-33 and simultaneously alter the distribution of the IL-33 receptor ST2. Specifically, smoke decreased ST2 expression on group 2 innate lymphoid cells (ILC2s) while elevating ST2 expression on macrophages and natural killer (NK) cells, thus altering IL-33 responsiveness within the lung. Consequently, upon infection and release, increased local IL-33 significantly amplified type I proinflammatory responses via synergistic modulation of macrophage and NK cell function. Therefore, in COPD, smoke alters the lung microenvironment to facilitate an alternative IL-33-dependent exaggerated proinflammatory response to infection, exacerbating disease.
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- Kolbeck, Roland, et al.
(författare)
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MEDI-563, a humanized anti-IL-5 receptor alpha mAb with enhanced antibody-dependent cell-mediated cytotoxicity function
- 2010
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Ingår i: Journal of Allergy and Clinical Immunology. - : Elsevier BV. - 1097-6825 .- 0091-6749. ; 125:6, s. 1344-1353
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Tidskriftsartikel (refereegranskat)abstract
- Background: Peripheral blood eosinophilia and lung mucosal eosinophil infiltration are hallmarks of bronchial asthma. IL-5 is a critical cytokine for eosinophil maturation, survival, and mobilization. Attempts to target eosinophils for the treatment of asthma by means of IL-5 neutralization have only resulted in partial removal of airway eosinophils, and this warrants the development of more effective interventions to further explore the role of eosinophils in the clinical expression of asthma. Objective: We sought to develop a novel humanized anti IL-5 receptor alpha (IL-5R alpha) mAb with enhanced effector function (MEDI-563) that potently depletes circulating and tissue. resident eosinophils and basophils for the treatment of asthma. Methods: We used surface plasmon resonance to determine the binding affinity of MEDI-563 to Fc gamma RIII alpha. Primary human eosinophils and basophils were used to demonstrate antibody-dependent cell-mediated cytotoxicity. The binding epitope of MEDI-563 on IL-5R alpha was determined by using site-directed mutagenesis. The consequences of MEDI-563 administration on peripheral blood and bone marrow eosinophil depletion was investigated in nonhuman primates. Results: MEDI-563 binds to an epitope on IL-5R alpha that is in close proximity to the IL-5 binding site, and it inhibits IL-5 mediated cell proliferation. MEDI-563 potently induces antibody-dependent cell-mediated cytotoxicity of both eosinophils (half-maximal effective concentration = 0.9 pmol/L) and basophils (half-maximal effective concentration = 0.5 pmol/L) in vitro. In nonhuman primates MEDI-563 depletes blood eosinophils and eosinophil precursors in the bone marrow. Conclusions: MEDI-563 might provide a novel approach for the treatment of asthma through active antibody-dependent cell-mediated depletion of eosinophils and basophils rather than through passive removal of IL-5. (J Allergy Clin Immunol 2010;125:1344-53.)
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- Levitsky, A., et al.
(författare)
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Using patients' own knowledge of early sensations and symptoms to develop an interactive, individualized e-questionnaire to facilitate early diagnosis of lung cancer
- 2021
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Ingår i: BMC Cancer. - : Springer Science and Business Media LLC. - 1471-2407. ; 21:1
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundOne reason for the often late diagnosis of lung cancer (LC) may be that potentially-indicative sensations and symptoms are often diffuse, and may not be considered serious or urgent, making their interpretation complicated. However, with only a few exceptions, efforts to use people's own in-depth knowledge about prodromal bodily experiences has been a missing link in efforts to facilitate early LC diagnosis. In this study, we describe and discuss facilitators and challenges in our process of developing and initial testing an interactive, self-completion e-questionnaire based on patient descriptions of experienced prodromal sensations and symptoms, to support early identification of lung cancer (LC).MethodsE-questionnaire items were derived from in-depth, detailed explorative interviews with individuals undergoing investigation for suspected LC. The descriptors of sensations/symptoms and the background items obtained were the basis for developing an interactive, individualized instrument, PEX-LC, which was refined for usability through think-aloud and other interviews with patients, members of the public, and clinical staff.ResultsMajor challenges in the process of developing PEX-LC related to collaboration among many actors, and design/user interface problems including technical issues. Most problems identified through the think-aloud interviews related to design/user interface problems and technical issues rather than content, for example we re-ordered questions to be in line with patients' chronological, rather than retrospective, descriptions of their experiences. PEX-LC was developed into a final e-questionnaire on a touch-screen smart tablet with one background module covering sociodemographic characteristics, 10 interactive, individualized modules covering early sensations and symptoms, and a 12th assessing current symptoms.ConclusionsClose collaboration with patients throughout the process was intrinsic for developing PEX-LC. Similarly, we recognized the extent to which clinicians and technical experts were also important in this process. Similar endeavors should assure all necessary competence is included in the core research team, to facilitate timely progress. Our experiences developing PEX-LC combined with new empirical research suggest that this individualized, interactive e-questionnaire, developed through systematizing patients' own formulations of their prodromal symptom experiences, is both feasible for use and has potential value in the intended group.
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