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Regulation of Eosinophil Mediator Release by Adhesion Molecules
Published in Bruce S. Bochner, Adhesion Molecules in Allergic Disease, 2020
Eosinophil peroxidase differs from neutrophil or monocyte myeloperoxidase (MPO) in its absorption spectrum and its heme prosthetic groups (24). Analysis of EPO reveals the molecular masses of 12 and 53 kD for the heavy and light subunits, respectively; their calculated isoelectric points are 10.8 and 10.7, respectively (25). In the presence of H2O2, EPO is able to oxidize halides to form reactive hypohalous acids (26). Analyses of EPO’s halide preference shows that eosinophils preferentially utilize bromide over chloride (27). This EPO/H2O2/halide system kills a variety of microorganisms, such as schistosomula of S. mansoni and Escherichia coli (28,29). Studies of cultured human pneumocytes (30), nasal epithelial cells (31), and tumor cells (32) indicate that the EPO/H2O2/halide system causes toxicity to mammalian cells. Eosinophils by themselves can generate H2O2 (33) suggesting that this EPO/H2O2/halide system is an effective system to mediate toxicity toward numerous targets. In the absence of H2O2 and halide, EPO is also toxic to some targets although the activity seems somewhat limited. Eosinophil peroxidase, as well as MBP, is a potent stimulus for human platelets and eosinophils (14,15)
The Host Immune Response Against Parasitic Helminth Infection
Published in Peter D. Walzer, Robert M. Genta, Parasitic Infections in the Compromised Host, 2020
The eosinophil granule-associated proteins–major basic protein, eosinophil cationic protein, and the eosinophil-derived neurotoxin–are each directly cytotoxic to parasites in vitro as is eosinophil peroxidase either in conjunction with H2O2 and halide, or directly through its phospholipid-cleaving enzymes (55, 56). Furthermore, several factors enhance the eosinophil's helminthotoxic capacity. Mast cell-associated mediators have been shown to enhance both antibodyand complement-dependent eosinophil-mediated cytotoxicity (93). Factors derived from T cells, such as eosinophil stimulation promoter (94), eosinophil differentiation factor (EDF) (95), and GM-CSF (96), have also been implicated in the enhancement of eosinophil-mediated killing. Furthermore, factors derived from monocytes also enhance eosinophil-mediated cytotoxicity. In particular, both tumor necrosis factor (97) and a 40-kD protein termed eosinophil activating factor (98) have each been used successfully in this regard.
Mucosal basophils, eosinophils, and mast cells
Published in Phillip D. Smith, Richard S. Blumberg, Thomas T. MacDonald, Principles of Mucosal Immunology, 2020
Edda Fiebiger, Stephan C. Bischoff
The granules of eosinophils contain major basic protein, eosinophil cationic protein, eosinophil-derived neurotoxin, eosinophil peroxidase, and other enzymes of uncertain significance, as well as proteins that include a broad range of preformed cytokines and chemokines (Figure 14.4). Major basic protein is cytotoxic for helminthic parasites and mammalian cells, activates the complement cascade, and leads to increased smooth muscle reactivity by causing dysfunction of vagal muscarinic M2 receptors. Moreover, major basic protein has been shown to stimulate substance P release from neonatal rat dorsal root ganglia neurons. Eosinophil cationic protein, eosinophil peroxidase, and eosinophil-derived neurotoxin induce cytotoxic effects in helminthic parasites and mammalian cells by exerting ribonuclease activity or generating unstable oxygen radicals. Among the cytokines and chemokines produced by eosinophils are IL-1α, IL-2, IL-3, IL-4, IL-5, IL-6, IL-9, IL-10, IL-12, IL-16, interferon-γ (IFN-γ), GM-CSF, TNF-α, eotaxin (CCL11), IL-8 (CXCL8), macrophage inflammatory protein-1α (MIP-1α), RANTES (CCL5), nerve growth factor, stem cell factor (SCF), platelet-derived growth factor (PDGF), and transforming growth factor (TGF)-α and TGF-β1, among others.
Primary tumors from mucosal barrier organs drive unique eosinophil infiltration patterns and clinical associations
Published in OncoImmunology, 2021
Sharon Grisaru-Tal, Michal Itan, Daniel G Grass, Javier Torres-Roca, Steven A Eschrich, Yaara Gordon, Avishay Dolitzky, Inbal Hazut, Shmuel Avlas, Elizabeth A Jacobsen, Tomer Ziv-Baran, Ariel Munitz
In contrast to colon cancer, our study revealed that eosinophil density in breast cancer was positively correlated with clinical stage and tumor size. These data suggest tumor-promoting activities for eosinophils in primary breast cancer. Moreover, stromal eosinophils were decreased in high estrogen receptor expression tumors. A proposed mechanism for the pro-tumorigenic activities of eosinophils in primary breast cancer was described using the 4T1 syngeneic murine orthotopic breast cancer model.55 Eosinophil peroxidase increased mammary tumor growth and enhanced lung metastases.55 Furthermore, in-vitro, peroxidase treatment stimulated robust migration of human mammary fibroblasts by inducing transcription of pro-tumorigenic and metastatic MMP1, MMP3, and COX-2 genes.55 In support of a tumor-promoting role for eosinophils in primary breast tumors, previous epidemiological studies suggested a link between increased expression of IL-5, a key eosinophil survival, and priming factor,56 in breast carcinomas and higher rates of distant metastasis and recurrence.57 Additionally, evaluation of human breast cancer revealed that a high proportion of tumors contained extensive, occult deposition of eosinophil peroxidase.58 Collectively, we set forth the notion that the opposing roles of eosinophils in distinct tumors is a result of functional heterogeneity determined by the physiological microenvironment as opposed to technical variance in detection methods.
Pharmacophore-based discovery of 2-(phenylamino)aceto-hydrazides as potent eosinophil peroxidase (EPO) inhibitors
Published in Journal of Enzyme Inhibition and Medicinal Chemistry, 2018
Daniela Schuster, Martina Zederbauer, Thierry Langer, Andreas Kubin, Paul G. Furtmüller
Eosinophil peroxidase was purified from human white blood cells to a purity index (A413/A280) of at least 1.0 as described by Olsen and Little27. Its concentration was calculated using ε413 nm 110 000 M−1 cm−128 Hydrogen peroxide, obtained as a 30% solution from Sigma Chemical Co., was diluted and the concentration determined by the absorbance measurement at 240 nm where the extinction coefficient is 39.4 M−1 cm−129. The other chemicals were also purchased from Sigma Chemical Co. at the highest grade available.
Efficacy and safety of benralizumab for eosinophilic asthma: A systematic review and meta-analysis of randomized controlled trials
Published in Journal of Asthma, 2018
Bao-ping Tian, Gen-sheng Zhang, Jian Lou, Hong-bin Zhou, Wei Cui
IL-5, which is mainly produced by Th2 and type 2 innate lymphoid cells (ILC2), is a cytokine that is specifically targeted at eosinophils, facilitating their terminal differentiation and maturation. In the process of an inflammatory response, more eosinophil recruitment and degranulation lead to the release of cytotoxic products, including major basic protein, eosinophil peroxidase, eosinophil cationic protein (ECP), eosinophil-derived neurotoxin (EDN), and various cytokines, chemokines and other mediators, which contribute to airway hyper-responsiveness, airway epithelial damage and mucus hyper-secretion [8, 12, 33]. Taken together, several hMabs targeting IL-5 and its receptor have been developed. Two hMabs directed against IL-5 include mepolizumab and reslizumab [3, 9, 28, 34–37]. Benralizumab is a recombinant IgG1 afucosylation antibody that is directed against the α chain of the IL-5 receptor. Afucosylation enhances the interaction of benralizumab with FcgRIIIa and heightens antibody-dependent cell-mediated cytotoxicity (ADCC) functions by greater than 1,000-fold compared with the parental antibody [38]. One reasonable explanation for this finding is that benralizumab is better able to enter tissues given its prolonged elimination half-life and large volume of distribution [39]. These benralizumab properties potentially clear airway eosinophils more completely and subsequently result in greater reductions of exacerbations and possibly improvements in other clinical symptoms of asthma. William et al. first reported that MEDI-563 (Benralizumab) had an acceptable safety profile and resulted in a marked reduction of peripheral blood eosinophil counts in subjects with mild asthma in a phase 1, multicenter, open-label study [40]. Subsequently, several RCTs of benralizumab in asthma control were developed [17–21, 31].