Anti-Interleukin-5 Antibody Therapy in Eosinophilic Diseases

Simon, Dagmar; Braathen, Lasse R.; Simon, Hans‐Uwe

doi:10.1159/000091326

Cited by 37 publications

(26 citation statements)

References 123 publications

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“…This finding indicates that eosinophils play a critical role in the airway remodeling in asthma. In addition, recently, anti-IL-5 mAb was shown to be beneficial in patients with hypereosinophilic syndrome [42, 43] and those with eosinophilic esophagitis [44, 45], re-affirming that the eosinophil represents a very important target cell for therapeutic intervention of diseases characterized by eosinophilia. …”

Section: Discussionmentioning

confidence: 99%

Rapid and Strong Induction of Apoptosis in Human Eosinophils by Anti-CD30 mAb-Coated Microspheres and Phagocytosis by Macrophages

Matsumoto

Terakawa²,

Fukuda³

et al. 2007

Int Arch Allergy Immunol

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Background: Eosinophils represent a potential therapeutic target in allergic diseases. We previously reported that two clones of anti-CD30 mAbs (HRS-4 and Ber-H8) induced extremely rapid and intense apoptosis in human eosinophils in vitro, but only when the mAbs were immobilized on plates [Matsumoto K, J Immunol 2004;172:2186]. As the initial step towards clinical application of these anti-CD30 mAbs in the treatment of allergic diseases, we made an attempt to clarify two issues; first, whether or not anti-CD30 mAb-coated microspheres can efficiently induce apoptosis in human eosinophils, and second, whether or not these apoptotic eosinophils can be phagocytosed by macrophages without the release of granular proteins. Methods: Purified human eosinophils were treated with anti-CD30 mAb-coated polystyrene microspheres (diameter, 1.44 µm). Apoptosis was determined by annexin V-binding. For the phagocytosis assay, eosinophils were co-cultured with monocyte-derived human macrophages or PMA-pretreated U-937 cells. Phagocytosis was determined by light microscopy and by the eosinophil-derived neurotoxin (EDN) concentration in the supernatant. Results: Anti-CD30 mAb-coated, but not control IgG1-coated microspheres significantly reduced eosinophil survival in a dose-dependent manner. Marked phagocytosis of the apoptotic eosinophils by macrophages was also observed when the eosinophils were treated with anti-CD30 mAb-coated microspheres. The apoptotic eosinophils released large amounts of EDN in the absence of macrophages; however, the EDN levels were significantly decreased when the eosinophils were co-cultured with macrophages. Conclusions: Anti-CD30 mAb-coated microspheres are capable of inducing rapid and strong apoptosis in human eosinophils. Furthermore, the apoptotic eosinophils were also phagocytosed by macrophages with minimal release of the granular proteins.

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Section: Discussionmentioning

confidence: 99%

Rapid and Strong Induction of Apoptosis in Human Eosinophils by Anti-CD30 mAb-Coated Microspheres and Phagocytosis by Macrophages

Matsumoto

Terakawa²,

Fukuda³

et al. 2007

Int Arch Allergy Immunol

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“…1,11,13 To investigate a potential role for syntenin in IL-5-driven eosinophilopoiesis, we cultured primary human cord blood-derived CD34 ϩ cells in the presence of IL-3 and IL-5 to induce eosinophil differentiation. In these cultures, syntenin was strongly up-regulated as indicated by Western blot analysis ( Figure 5A-B).…”

Section: Syntenin Is Critical For Eosinophil Differentiationmentioning

confidence: 99%

“…7-10 IL-5 specifically promotes eosinophil differentiation and survival from common myeloid progenitors, and plays a dominant role in the development of a subtype of B cells termed B1 cells. [11][12][13][14][15][16] Because the intracellular domains of IL-3R␣, GM-CSFR␣, and IL-5R␣ are unique, these are excellent candidates to mediate specific signaling pathways and cellular functions. We previously identified syntenin as specific interactor of intracellular IL-5R␣.…”

Section: Introductionmentioning

confidence: 99%

Regulation of myelopoiesis through syntenin-mediated modulation of IL-5 receptor output

Beekman

Verhagen²,

Geijsen

et al. 2009

Blood

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The granulocyte-macrophage colonystimulating factor (GM-CSF)/interleukin (IL)-3/IL-5 receptor family regulates the production and function of myeloid cells. These cytokines signal through receptor complexes that consist of unique ligandbinding ␣-chains and common signaling ␤-chains. IL-5 is distinct from IL-3 and GM-CSF in its capacity to induce eosinophil development, however, the molecular mechanisms that generate functional diversity within this receptor family are mostly unknown. Here, we characterized the selective IL-5R␣-binding adapter protein syntenin in IL-5R function. Syntenin and IL-5R␣ colocalize at the plasma membrane and in early endosomal compartments. Manipulation of syntenin expression by ectopic expression or knockdown selectively modulated IL-5R but not GM-CSF receptor signaling, and severely affected IL-5-induced eosinophil differentiation from primary human CD34 ؉ hematopoietic progenitor cells. We found syntenin upregulated during eosinophilopoiesis but down-regulated during neutropoiesis. Syntenin forms complexes with multiple IL-5R␣ chains, suggesting that synteninenhanced IL-5R output may result from stabilization of an IL-5-induced oligomeric receptor complex. These data demonstrate that cytokine-specific functions can be transduced by unique receptor ␣-chain-associating adapter proteins. (Blood. 2009;114:3917-3927) IntroductionLeukocyte functions are regulated by intracellular mechanisms that constantly integrate environmental signals. Cytokines and their receptors are key molecules in leukocyte communication that regulate hematopoiesis and immune responses. 1 Cytokine receptors have been classified on the shared use of common receptor components such as the common ␤-chain (␤c) for the granulocytemacrophage colony-stimulating factor receptor (GM-CSFR) family. 2 Tightly regulated and complex signaling networks have evolved to ensure robust cellular output of cytokine-mediated signaling input. Adapter and scaffold proteins play a decisive role in these networks by regulating the kinetics and specificity of signal transduction pathways. 3 These proteins consist of multiple protein interaction domains that lack enzymatic activity, and modulate the composition of protein complexes and thus which protein substrates are favorably targeted. Adapter molecules may allow the induction of receptor-specific signaling pathways, and cellular functions, however until now there are few examples.IL-3, IL-5, and GM-CSF are important regulators of myeloid cell differentiation and leukocyte function. 4 These cytokines bind to unique ␣-chains, and then recruit a common ␤-chain (␤c) to form high-affinity receptors. Receptor activation induces overlapping signaling pathways that depend on both ␣ and ␤c which are preassociated with Janus kinases (JAKs) that activate signal transducer and activators of transcription (STAT). 4,5 Other shared signaling pathways include the phosphoinositol-3 kinase (PI-3K)/ protein kinase B pathway (PKB/c-Akt) that is crucial for cellular survival, and mitogen-activated protein ki...

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“…Thus, the blocking or depleting IL-5 from asthmatic patients will result in both allergic inflammation and symptom remission. In fact, a few lines of investigations have shown that passive administration of anti-IL-5 monoclonal antibodies or experimental vaccines against IL-5 not only inhibited recruitment of eosinophils from the bone marrow into the targeted organs, but also attenuated allergic inflammation and clinical symptoms (Menzies-Gow et al, 2003;Simon et al, 2005;Sutton et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

RNA interference against interleukin-5 attenuates airway inflammation and hyperresponsiveness in an asthma model

Chen

Huang

Tan

et al. 2009

J. Zhejiang Univ. Sci. B

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Abstract:Interleukin-5 (IL-5) accompanies the development of airway inflammation and hyperresponsiveness through the activation of eosinophils. Therefore, interference of IL-5 expression in lung tissue seems to be an accepted approach in asthma therapy. In this study, we designed a small interfering RNA (siRNA) to inhibit the expression of IL-5. The siRNAs against IL-5 were constructed in a lentivirus expressing system, and 1.5×106 IFU (inclusion-forming unit) lentiviruses were administered intratracheally to ovalbumin (OVA)-sensitized murine asthmatic models. Our results show that lentivirus-delivered siRNA against IL-5 efficiently inhibited the IL-5 messenger ribonucleic acid (mRNA) expression and significantly attenuated the inflammation in lung tissue. Significant decrease of eosinophils and inflammatory cells were found in peripheral blood, bronchoalveolar lavage fluid (BALF), and lung tissue. In addition, significant inhibition of airway hyperresponsiveness (AHR) was found in the mice treated with siRNA against IL-5. These observations demonstrate that siRNA delivered by means of the lentivirus system is possibly an efficacious therapeutic approach for asthma.

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Anti-Interleukin-5 Antibody Therapy in Eosinophilic Diseases

Cited by 37 publications

References 123 publications

Rapid and Strong Induction of Apoptosis in Human Eosinophils by Anti-CD30 mAb-Coated Microspheres and Phagocytosis by Macrophages

Rapid and Strong Induction of Apoptosis in Human Eosinophils by Anti-CD30 mAb-Coated Microspheres and Phagocytosis by Macrophages

Regulation of myelopoiesis through syntenin-mediated modulation of IL-5 receptor output

RNA interference against interleukin-5 attenuates airway inflammation and hyperresponsiveness in an asthma model

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