Author
Jaideep Dhariwal
Other affiliations: Guy's and St Thomas' NHS Foundation Trust, King's College London, Imperial College Healthcare ...read more
Bio: Jaideep Dhariwal is an academic researcher from Guy's Hospital. The author has contributed to research in topics: Benralizumab & Asthma. The author has an hindex of 13, co-authored 35 publications receiving 986 citations. Previous affiliations of Jaideep Dhariwal include Guy's and St Thomas' NHS Foundation Trust & King's College London.
Topics: Benralizumab, Asthma, Medicine, Mepolizumab, Exacerbation
Papers
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TL;DR: IL-33 and type 2 cytokines are induced during a rhinovirus-induced asthma exacerbation in vivo and relate to exacerbation severity, which is a novel therapeutic approach for asthma exacerbations.
Abstract: Rationale: Rhinoviruses are the major cause of asthma exacerbations; however, its underlying mechanisms are poorly understood. We hypothesized that the epithelial cell–derived cytokine IL-33 plays ...
473 citations
TL;DR: It is found that CD8+ Trm cells in the human lung can confer protection against severe respiratory viral disease when humoral immunity is overcome, implying that the immunodominance hierarchy can be defined.
Abstract: In animal models, resident memory CD8+ T (Trm) cells assist in respiratory virus elimination but their importance in man has not been determined. Here, using experimental human respiratory syncytial virus (RSV) infection, we investigate systemic and local virus-specific CD8+ T-cell responses in adult volunteers. Having defined the immunodominance hierarchy, we analyse phenotype and function longitudinally in blood and by serial bronchoscopy. Despite rapid clinical recovery, we note surprisingly extensive lower airway inflammation with persistent viral antigen and cellular infiltrates. Pulmonary virus-specific CD8+ T cells display a CD69+CD103+ Trm phenotype and accumulate to strikingly high frequencies into convalescence without continued proliferation. While these have a more highly differentiated phenotype, they express fewer cytotoxicity markers than in blood. Nevertheless, their abundance before infection correlates with reduced symptoms and viral load, implying that CD8+ Trm cells in the human lung can confer protection against severe respiratory viral disease when humoral immunity is overcome.
207 citations
TL;DR: In a large real-world SEA cohort, benralizumab led to significant improvements in all clinical outcome measures and the optimal regression model of super-responders versus other responders included baseline characteristics associated with a strongly eosinophilic phenotype and less severe disease.
136 citations
TL;DR: In a real-world SEA cohort, treatment with mepolizumab reduced exacerbation frequency and mOCS requirements and Nasal polyposis, a lower BMI and a lower maintenance prednisolone requirement at baseline were associated with better outcomes.
107 citations
TL;DR: Precision sampling of mucosal lining fluid identifies robust interferon and type 2 responses in the upper and lower airways of asthmatics during an asthma exacerbation.
96 citations
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TL;DR: 15 years of discoveries on IL‐33 protein are highlighted, including its molecular characteristics, nuclear localization, bioactive forms, cellular sources, mechanisms of release and regulation by proteases, and important roles in allergic, fibrotic, infectious, and chronic inflammatory diseases.
Abstract: Interleukin-33 (IL-33) is a tissue-derived nuclear cytokine from the IL-1 family abundantly expressed in endothelial cells, epithelial cells and fibroblast-like cells, both during homeostasis and inflammation. It functions as an alarm signal (alarmin) released upon cell injury or tissue damage to alert immune cells expressing the ST2 receptor (IL-1RL1). The major targets of IL-33 in vivo are tissue-resident immune cells such as mast cells, group 2 innate lymphoid cells (ILC2s) and regulatory T cells (Tregs). Other cellular targets include T helper 2 (Th2) cells, eosinophils, basophils, dendritic cells, Th1 cells, CD8+ T cells, NK cells, iNKT cells, B cells, neutrophils and macrophages. IL-33 is thus emerging as a crucial immune modulator with pleiotropic activities in type-2, type-1 and regulatory immune responses, and important roles in allergic, fibrotic, infectious, and chronic inflammatory diseases. The critical function of IL-33/ST2 signaling in allergic inflammation is illustrated by the fact that IL33 and IL1RL1 are among the most highly replicated susceptibility loci for asthma. In this review, we highlight 15 years of discoveries on IL-33 protein, including its molecular characteristics, nuclear localization, bioactive forms, cellular sources, mechanisms of release and regulation by proteases. Importantly, we emphasize data that have been validated using IL-33-deficient cells.
504 citations
TL;DR: The cytokine networks driving asthma are reviewed, placing these in cellular context and incorporating insights from cytokine-targeting therapies in the clinic, to argue that the development of new and improved therapeutics will require understanding the diverse mechanisms underlying the spectrum of asthma pathologies.
501 citations
TL;DR: To elucidate the efficacy, safety, and patient characteristics of responsiveness to mepolizumab (a humanized monoclonal antibody against interleukin 5), a large number of patients with severe, eosinophilic asthma were enrolled in 81 multinational centers.
Abstract: ID Pavord, S Korn, P Howarth. Lancet. 2012;380(9842):651–659
To elucidate the efficacy, safety, and patient characteristics of responsiveness to mepolizumab (a humanized monoclonal antibody against interleukin 5). Previous small, proof-of-concept studies in subjects with severe, eosinophilic asthma revealed that mepolizumab decreased exacerbation rates.
From 81 multinational centers, 621 pa-tients were enrolled. Major inclusion criteria included: age 12 to 74 years, asthma diagnosis with objective measures, ≥2 asthma exacerbations requiring oral corticosteroids in the last year, refractory asthma as defined by the American …
387 citations
TL;DR: CD8+ and CD4+ Trm ontogeny, maintenance, function, and distribution within lymphoid and nonlymphoid tissues and strategies for their study are reviewed.
Abstract: Resident memory T (Trm) cells stably occupy tissues and cannot be sampled in superficial venous blood. Trm cells are heterogeneous but collectively constitute the most abundant memory T cell subset...
355 citations
TL;DR: The key phenotypic, transcriptional, and functional features of these tissue-resident memory T cells as established in mouse models of infection and translated to humans by novel tissue sampling approaches are discussed.
Abstract: The discovery of T cells resident in diverse tissues has altered our understanding of adaptive immunity to encompass site-specific responses mediated by tissue-adapted memory T cells throughout the body. Here, we discuss the key phenotypic, transcriptional, and functional features of these tissue-resident memory T cells (TRM) as established in mouse models of infection and translated to humans by novel tissue sampling approaches. Integration of findings from mouse and human studies may hold the key to unlocking the potential of TRM for promoting tissue immunity and preventing infection.
349 citations