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The Pharmacotherapy of Rhinitis and Asthma
Published in Pudupakkam K Vedanthan, Harold S Nelson, Shripad N Agashe, PA Mahesh, Rohit Katial, Textbook of Allergy for the Clinician, 2021
Amanda Grippen Goddard, Harold S. Nelson, Rohit Katial, Flavia Hoyte
The monoclonal anti-IgE, omalizumab, is approved in the US only for use in patients with severe allergic asthma and chronic idiopathic urticaria, but several studies have confirmed its efficacy in allergic rhinitis either alone or in combination with allergen immunotherapy. Most studies showed a reduction in nasal symptom scores, reduced medication use and improved quality of life scores (Benninger et al. 2010, Wise et al. 2018). When used in combination with allergen immunotherapy, omalizumab significantly reduced symptom load as compared with allergen immunotherapy alone, independent of the allergen (Kopp et al. 2009). The high cost of therapy precludes a widespread use of omalizumab in allergic rhinitis. Dupilumab, an anti-IL-4 receptor α monoclonal antibody which inhibits IL-4 and IL-13 signaling, has been approved for use in patients with eosinophilic or steroid-dependent asthma, atopic dermatitis or nasal polyposis. Although it has been shown to improve allergic rhinitis-associated nasal symptoms in patients with uncontrolled persistent asthma and comorbid perennial allergic rhinitis, its widespread use will also be cost-prohibitive (Weinstein et al. 2018).
Interleukin-10 and Other Suppressive Cytokines
Published in Helmut Brade, Steven M. Opal, Stefanie N. Vogel, David C. Morrison, Endotoxin in Health and Disease, 2020
Arnaud Marchant, Michel Goldman, Tom van der Poll
IL-4 and IL-13 are structurally and functionally related cytokines produced by T lymphocytes, which share a number of biological activities including the inhibition of cytokine production by blood mononuclear cells (24). This effect appears to be more complex than in the case of IL-10 and depends upon the experimental conditions. Indeed, TNF production is suppressed when monocytes are coincubated in the presence of LPS and IL-4 or IL-13 but is increased when cells are preincubated in the presence of the cytokines (24,25). A similar phenomenon has been described for IL-10; IL-13 and IL-4 decrease IL-10 production or increase IL-10 production by mouse macrophages after coincubation or preincubation (25). Data reported by Muchamuel et al. indicate that IL-13 inhibits TNF production and protects mice from LPS-induced lethality (92). The role of IL-4 and IL-13 in the biology of LPS and during severe bacterial infections is not yet established. Several authors have failed to demonstrate increased levels of IL-4 or IL-13 in the circulation of LPS-challenged human volunteers or in patients with septic shock, but these data do not exclude local production of the cytokines in affected organs (62,71).
Gene Therapy for Lung Cancer
Published in Kenneth L. Brigham, Gene Therapy for Diseases of the Lung, 2020
Choon Taek Lee, David P. Carbone
IL-4 also shows antitumor effects in animal tumor models. IL-4 is produced by Th2 subset of helper T-cells and mast cells, and has many functions. It can induce LAK cells, stimulate B cell proliferation and maturation, and activate endothelial cells to express vascular cell adhesion molecules (24). Tepper et al. (25) demonstrated that IL-4 production from transfected tumor cells had antitumor effects in various tumor cell lines. This effect is blocked by anti-IL-4 antibody, related to the level of the production, and is evident in nude mice. Infiltration of the transduced tumor site with macrophages and eosinophils suggested that inflammatory mechanisms were involved.
Exploring the role of Janus kinase (JAK) in atopic dermatitis: a review of molecular mechanisms and therapeutic strategies
Published in Immunological Medicine, 2023
Toshiaki Kogame, Gyohei Egawa, Kenji Kabashima
Tralokinumab, a monoclonal antibody that neutralizes IL-13, became available for AD treatment. In ECZTRA 1 (NCT03131648) and ECZTRA 2 (NCT03160885, identical phase 3 randomized, double-blind trials, the more AD patients who were treated with tralokinumab achieved IGA reduction to 1 or less (ECZTRA 1: 15.8% and ECZTRA 2: 22.2%) than placebo-treated patients (ECZTRA 1: 7.1% and ECZTRA 2: 10.9%) at 16 weeks. EASI75 was also more achieved by the tralokinumab-treated group (ECZTRA 1: 25.0% and ECZTRA 2: 33.2%) than placebo-treated group (ECZTRA 1: 12.7% and ECZTRA 2: 11.4%) at 16 weeks [37]. Previously, IL-4 was considered a pivotal cytokine for AD pathogenesis. However, recent data from experimental settings indicate that IL-13 is a primary cytokine to play a role in AD [38]. On the contrary, clinical data implies that dupilumab seems more efficient in achieving EASI75 than tralokinumab. Nonetheless, a direct comparison of tralokinumab with dupilumab has not been conducted.
Investigational anti IL-13 asthma treatments: a 2023 update
Published in Expert Opinion on Investigational Drugs, 2023
Maria Gabriella Matera, Josuel Ora, Luigino Calzetta, Paola Rogliani, Mario Cazzola
Although IL-13 is an important therapeutic target for asthma, anti-IL-13 mAbs have numerous limitations. On the other hand, attempts to create mAbs treatments for asthma that focused on blocking IL-4 were equally relatively ineffective [98]. The overlapping biological roles of IL-4 and IL-13 are most likely responsible for their partial impacts [99]. IL-4 and IL-13 directly activate the canonical JAK/STAT pathways and increase proinflammatory gene expression and effector actions via activating other signaling cascades. These different signaling pathways influence many distinct aspects of the cellular and molecular responses connected to IL-4/IL-13. We can develop drugs that target pathologic outcomes or develop therapies for treating rare disease endotypes more effectively if we have a thorough understanding of IL-4/IL-13 signaling pathways, including the precise circumstances under which noncanonical signaling pathways are activated.
Should atopic dermatitis patients starting JAK inhibitors take prophylactic acyclovir?
Published in Journal of Dermatological Treatment, 2021
Milaan A. Shah, Katherine G. Beuerlein, Joseph L. Jorizzo, Steven R. Feldman
Janus kinases (JAK) are a group of intracellular non-receptor tyrosine kinases involved in the modulation of cytokines which play an integral role in immune and inflammatory processes (1–3). Many autoimmune conditions are precipitated by an imbalance in cytokine function (2). Obstructing this process with JAK inhibiting monoclonal antibodies can be of benefit in the treatment of conditions such as rheumatoid arthritis and inflammatory bowel disease (4). JAK inhibitors repress the signaling of numerous cytokines including IL-4, IL-5, IL-13, IFN-β, and IFN-γ (2,3,5), (Table 1). Interferon gamma (IFN-g) has a key role in preventing viral replication which make it important for limiting infection with and preventing reactivation of viruses, such as herpes viruses (6). Other varieties of monoclonal antibodies target fewer components of the inflammatory pathway. For example, dupilumab, used in atopic dermatitis treatment, inhibits only IL-4 and IL-13, allowing for more targeted immune modulation (7). Thus, dupilumab has a decreased risk of serious infection and no increased risk of overall infection (7,8). While widespread cytokine inhibition by JAK inhibitors allows them to be employed for numerous indications, this advantage is balanced with their less specific immune modulatory effect and increased risk of infection (2,8), (Figure 1).