IL-5, a cytokine that belongs to the common-chain family, together with IL-3 and granulocyte-macrophage colony-stimulating factor (GM-CSF), stimulates also the activation and survival of eosinophils [Yamaguchi 1991] and, to some extent, of basophils [Bischoff 1990; Hirai 1990]

IL-5, a cytokine that belongs to the common-chain family, together with IL-3 and granulocyte-macrophage colony-stimulating factor (GM-CSF), stimulates also the activation and survival of eosinophils [Yamaguchi 1991] and, to some extent, of basophils [Bischoff 1990; Hirai 1990]. the production of IL-5. Keywords: asthma, eosinophilia, exacerbations, IL-5, mepolizumab, personalized medicine, severe asthma, targeted therapy Introduction Paul Ehrlich announced the discovery of the eosinophil in a presentation to the Physiological Society of Berlin AZD5582 on 17 January 1879 [Ehrlich, 1879a]. His next paper contained an extensive description of these cells [Ehrlich, 1879b]. Ehrlich identified peripheral blood eosinophils thanks to their capacity to be stained by eosin. He suggested that eosin interacted, like a magic bullet, with a specific eosinophil receptor. Ehrlichs hypothesis of chemical affinities in biological processes is epitomized in his maxim 2015]. IL-5, a cytokine that belongs to the common-chain family, together with IL-3 and granulocyte-macrophage colony-stimulating factor (GM-CSF), stimulates also the activation and survival of eosinophils [Yamaguchi 1991] and, to some extent, of basophils [Bischoff 1990; AZD5582 Hirai 1990]. IL-5 binds to a heterodimer receptor composed by the specific subunit IL-5R and a common subunit c shared with IL-3 and GM-CSF [Rosas 2006; Takatsu, 2013]. Human eosinophils express AZD5582 approximately a three-fold higher level of IL-5R compared with basophils [Kolbeck 2010]. Major sources of IL- 5 are T-helper 2 (Th2) cells, mast cells, CD34+ progenitor cells, invariant natural killer (NK) T-cells, group 2 innate lymphoid cells (ILC2s), and eosinophils themselves [Fallon 2013; Phillips 2003]. ILC2s control not only eosinophil number but also their circadian cycling through the production of IL-5 [Nussbaum 2013]. Mepolizumab in adults with eosinophilic asthma Given the critical role of IL-5 in influencing several activities of eosinophils, this cytokine and its receptor attracted the attention of pharmaceutical industries as a possible target in the treatment of hypereosinophilic diseases including eosinophilic asthma [Varricchi 2016]. Mepolizumab (Nucala; GlaxoSmithKline, London, UK) was the first anti-IL-5 humanized monoclonal antibody described over 15 years ago [Zia-Amirhosseini 1999]. Mepolizumab binds to IL-5 with high specificity (maximal inhibitory concentration <1 nm) and affinity (approximately 4.2 pM), thus preventing its binding to the chain of the IL-5R complex on eosinophils and basophils. A preclinical study on the pharmacology and safety of mepolizumab in na?ve and monkeys demonstrated that a single intravenous (iv) dose reduced blood eosinophilia for 6 weeks without affecting acute bronchoconstriction [Hart 2001]. Two initial studies evaluated, in a randomized, double-blind, parallel group, the effects of iv anti-IL-5 in a small group of mild asthmatic patients (Table 1). Although anti-IL-5 produced a decrease in blood eosinophils and partial reduction of airway and bone marrow eosinophils, there were no effects on airway hyperresponsiveness (AHR) and late response to inhaled allergens [Flood-Page 2003; Leckie 2000]. Similarly, in a multicenter study to evaluate safety and efficacy of iv mepolizumab in patients with moderate persistent asthma, the treatment produced a rapid and marked reduction in blood eosinophils, without improving lung functions and symptoms [Flood-Page 2007]. These initial studies produced frustrating results, and several investigators questioned the efficacy of this targeted therapy on asthma treatment [Flood-Page 2003; Wenzel, 2009]. In fact, no significant effects were AZD5582 found in terms of AHR, peak expiratory flow (PEF), and forced expiratory volume in one second (FEV1) despite a remarkable reduction in blood eosinophilia [Flood-Page 2003; Leckie 2000]. Table 1. Clinical trials of mepolizumab in asthma. 2003]Mild asthmatics750 mg iv every 4 weeks for 3 months Eosinophils within bronchial mucosa[Flood-Page 2003]Mild asthmatics750 mg iv every 4 weeks for 3 months Blood eosinophils Airway eosinophils by 50%No effect on PEF, FEV1 and bronchial hyperresponsiveness[Flood-Page 2007]Moderate asthmatics250 or 750 mg iv every 4 weeks for 3 months Blood and sputum eosinophilsNo effect on PEF, FEV1 and AQLQ[Haldar 2009]Severe eosinophilic asthmatics750 mg iv every 4 weeks for 1 year Rabbit Polyclonal to CNGA2 Blood eosinophils Exacerbations AQLQNo effect on FEV1[Nair 2009]Prednisone-dependent eosinophilic asthmatics750 mg iv every 4 weeks for 5 months Blood and sputum eosinophils ExacerbationsPrednisone-sparing effect[Pavord 2012]Severe eosinophilic asthmatics1 of 3 doses (750, 250 or 75 mg) iv every 4 weeks for 13 months Blood and sputum Eosinophils ExacerbationsNo effect on FEV1 and AQLQ[Ortega 2014b]Severe AZD5582 eosinophilic asthmaticsMENSA STUDY100 mg sc every 4 weeks for 8 months Blood eosinophilia Exacerbations FEV1 ACQ-5 score[Bel 2014]Severe eosinophilic asthmaticsSIRIUS STUDY100 mg sc every 4 weeks for 6 months Blood eosinophils ExacerbationsGlucocorticoid sparing-effect ACQ-5 score[Haldar 2014]Severe eosinophilic asthmatics750 mg iv every 4 weeks Outcome after cessationRapid increase in blood and sputumeosinophils followed by.