Copyright ERS Journals LtdEuropean Respiratory JournalISSN 0903 1936 - PDF document

DOI:10.1183/09031936.94.07040743 Copyright ERS Journals LtdEuropean Respiratory JournalISSN 0903 - 1936 the eosinophil leucocyte (Part II) * Pulmonary immune cells in health and disease: the eosinophil leucocyte (Part II). C.Kroegel, J.A. Warner, J.-C. Virchow Jr, H. Matthys. ABSTRACT: The second part of this review on eosinophils focuses on biologicaleosinophil-dominated inflammatory reaction. It discusses the possible pathogenic i.Br., Germany. **Dept of Physiology andCorrespondence: C. Kroegel, Dept of This paper is published as a follow-on to "Pulmonaryimmune cells in health and disease: the eosinophil leu- In addition to their cytotoxic action, eosinophil cat-ionic proteins at certain subtoxic concentrations alsostimulate other inflammatory cells. For instance, MBP SERIES 'PULMONARY IMMUNE CELLS'Edited by U. Costabel and C. Kroegel *References [1] Ð [322], Figures 1Ð6 and Tables 1Ð6 are to be found in Part I. poran [174, 337, 338], the ninth component of comple-ment [339], and perforin 1 from natural killer and cytotoxicment [339], and perforin 1 from natural killer and cytotoxicO and staphylococcal -toxin [341].These proteins have in common a high affinity forstages: firstly the proteins approach the cell through theformation of electrostatic bonds between their positivelyphospholipids, glycolipids and glycoproteins [342,bilayer. The driving force for the hydrophobic interac-ation of both the hydrophobic core of the phospholipid[337, 344Ð346]. These protein-membrane interactions[337, 344Ð346]. These protein-membrane interactionsThese processes, in turn, may destabilize membranes,induce fusion of adjacent bilayers, activate phospho-lipase A2[131, 169, 347], and form voltage-insensitivetransmembrane ion channels [237, 340]. Once enoughtransmembrane ion channels [237, 340]. Once enoughcellular contents, or influx of Ca2+, is likely to takeplace, which eventually leads to cell death and lysis[174, 337). This mechanism of toxicity was first pro- ), and the other, the production of hypo-). In addition, newly formed[111]. In addition, in the presence of Hmicro-organisms. The EPO/HEscherichia coli,Staphylococcusas well as to fungi, the schistosomula of as well as to fungi, the schistosomula of The eosinophil is exceptionally rich in peroxidase,and the enzyme is released both by soluble stimuli [73,110, 131, 135, 169], and by adhesion to

larger opson-ized targets [2, 30, 33, 56, 159, 169, 208, 349, 350].EPO is a highly basic protein that binds avidly to neg-atively charged surfaces with retention of peroxidaseactivity. In the presence of Hgondii, T. cruzi, mour cells [2, 99, 349, 350]. In addition, the toxic effect[97, 98, 349]. Finally, EPO can associate with mast cell KROEGELETAL (MBP, ECP, collagenase)mechanisms (LTCPAF) Bronchial disease (asthma) Fig. 7. Ð Nonoxidative, oxidative and lipid mediator-associated effector functions of eosinophil leucocytes on bronchial and leukotriene C4(LTC4) [115, 117, 120], prostaglandinEE1(PGF1) and throm-boxane A2(TxA2) [119Ð121, 123]. Using compillary gas chromatography/mass spectrometry, twoillary gas chromatography/mass spectrometry, twomay induce certain pathophysiological effects in vivo.Eosinophil-derived PAF, LTC4or TxA2, PGD2, and PGF2,for instance, may contribute to tissue inflammation,bronchoconstriction or bronchial hyperreactivity in late-phase asthmatic reactions where eosinophils are charac-teristically found. PGE has been shown to down-regulateteristically found. PGE has been shown to down-regulateEosinophil-dominated inflammatory reactionAs outlined above, considerable circumstantial evi-dence implicates the eosinophil as a major effector cellin various diseases of the lung. Eosinophils can releaseinterstitial lung disorders. The underlying immune mech- . Plasma cells maysion molecules such as CD 11b, . At the same time,derived IgE, bind specific antigen, triggering the rel-response. The concerted action of cytokines and PAF. After arrival at the inflammatoryhyporeactive, due to cell desensitization mediated by PULMONARYIMMUNECELLSEOSINOPHILLEUCOCYTE Antigen PAF PAF ABRolling PAF PAF T- 3 bronchitisEosinophilicpneumonia Vasculitis TNF Exogenous or Endogenous(extrinsic asthma) (eosinophilic pneumonia) PAF TGFEffector Fig. 8. Ð Putative mechanisms of the eosinophil-dominated inflammatory reaction. For details see text. B-lym: B-lymphocytes; EPO:eosinophil peroxidase; GM-CSF: granulocyte-macrophage colony-stimulating factor; IFN-; IgE: immunoglobulin E; IL:interleukin; MBP: major basic protein; PAF: platelet-activating factor; TNF: tumour necrosis factor; TGF: tumour-growth fact chemotactic factors such as PAF. The continued expo-eosinophil to regain i

ts proinflammatory properties, na-mely the release of granule proteins, cytokines, lipidly the release of granule proteins, cytokines, lipidon the respective antigen, the infiltrated tissue and itshistological properties and physiological function, eosin-ophil-derived products may either cause destruction ofairway epithelium (bronchial asthma), F, interstitial de-struction and oedema (eosinophilic pneumonia, parasiticinfestation), Gand H, or granulomatous tissue destruc-tion in certain vasculitic disorders (Churg-Strauss syn-drome), I. Toxic products secreted by the eosinophil may. In addition, eosinophil- matous diseases [2, 326, 351Ð368]. The potential role(tropical filarial eosinophilia) [359]. Four main findingshave emerged over the past two decades. Firstly, anti-al blood eosinophils and increases susceptibility toal blood eosinophils and increases susceptibility toved in the killing of helminths [323, 360]. Thirdly,cytotoxic for parasites [361, 362]. Finally, eosinophilscytotoxic for parasites [361, 362]. Finally, eosinophils364]. These data appear to support a role for the eosinophilof cytokines [365, 366] on the immunity to helminths inAdministration of anti-IL-5 and anti-IL-4 antibodiesas serum IgE levels, but failed to diminish immunityto the parasite. In contrast to these findings, treatmentto the parasite. In contrast to these findings, treatmentAlthough mice may employ different immune mecha-nisms for parasite resistance, the apparent discrepancywith previous work clearly warrants further clarification.The mechanism whereby eosinophils destroy para-sites can be divided into recognition, attachment andkilling phases. Recognition is facilitated by chemotac-cells and by parasite-derived factors. In addition,cells and by parasite-derived factors. In addition,ment proteins [369], facilitate the attachment of theeosinophil to the parasite. Adhering eosinophils flattenand release granule proteins [370, 371], and oxygen rad-icals [99, 108, 372], onto the surface of the parasiteeventually leading to its destruction.Interstitial lung disordersAlthough eosinophils are rarely found in the normalhuman lower respiratory tract, accumulation of eosin-ophils in the parenchyma is found in the course of var-ious inflammatory diseases [373, 374]. Besides the KROEGELETAL Table 7. Ð List of eosinophil-associated respiratory dis- structures and th

e interstitium [355, 356]. The reasonsease. Eosinophils are normally found in the bron-that of neutrophils [377]. In addition, eosinophils havethat of neutrophils [377]. In addition, eosinophils have378]. The levels of ECP in BAL fluid from patientsthy controls, and its concentration correlates with are-duction in diffusion capacity of the lung [379]. Although the cause of eosinophil accumulation insome of these disorders is unknown, increasing evidencesuggests that the eosinophil can function as an effectorcell capable of mediating direct interstitial tissue de-struction. A role for eosinophils in mediating injury toparenchyma [326, 328]. In general, two differentmechanisms may be involved. Firstly, the eosinophilman lung collagens type I and III [326, 381]. Secondly,of reactive oxygen radicals. For instance, eosinophilsand epithelial cells [325, 326, 328, 330, 382]. Eosinoand epithelial cells [325, 326, 328, 330, 382]. Eosinodative and nonoxidative effector mechanisms.Eosinophilic pneumoniatrum of disorders clinically characterized by systemictrum of disorders clinically characterized by systemicdromes is an infiltrative eosinophilia [384], accom-panied by an increased number of eosinophils in bloodand BAL [148, 154, 265, 385, 386]. Treatment withrence [383, 387, 388]. the underlying pathomechanisms of the disease. Thisthe underlying pathomechanisms of the disease. Thisin areas of eosinophilic microabscesses [327, 388], nu-merous lysed eosinophils [265], and free granuleswithin the pulmonary microvasculature, as well as de-posits of MBP in parenchymal lesions [389Ð392]. Inposits of MBP in parenchymal lesions [389Ð392]. In265], are predominantly hypodense [37, 148, 154, 265],and express several activation markers, including inter-cellular adhesion molecule-1 (ICAM-1), CD 11b, aswell as the major hisocompatibility class II antigen,HLA-DR [37, 140], suggesting a profound activation ofpulmonary eosinophils in this disease.The above observations are complemented by in vitrostudies, which show that eosinophil-derived granular pro-teins can directly injure pulmonary endothelial cells,increase the transvascular flux of proteins across endo-thelial monolayers, and cause lung oedema in isolatedperfused rat lungs [393, 394]. Hence, eosinophils maythe lung. In addition, since the class II protein HLA-yet unknown, antigen in eosinophilic pneumonia

.yet unknown, antigen in eosinophilic pneumonia.tizing vasculitic lesions in polyarteriitis nodosa andWegener's disease [396], systemic vasculitis of unknownorigin [397], and in temporal arteriitis [398]. Depositsthrombi. In contrast, eosinophils or their products cantrate within 4 days after implantation [399]. In man, PULMONARYIMMUNECELLSEOSINOPHILLEUCOCYTE graft survival [400Ð402]. In addition, an increase in thegraft survival [400Ð402]. In addition, an increase in theEosinophilic pleural effusionEosinophils are often observed in pleural effusion asso-ciated with pneumothorax, asbestosis, pulmonary in-farction, sarcoidosis and collagen vascular disease [404,405]. In addition, eosinophils occur in pleural effusionof unknown cause. Although the pathogenic significanceof pleural eosinophils is not yet clear, their presencenant disease or pulmonary tuberculosis [404Ð408]. Recentnant disease or pulmonary tuberculosis [404Ð408]. Recentadministration of interleukin-2 (IL-2) into the pleuralcavity has been shown to cause eosinophil accumu-lation indirectly viathe release of these cytokines bythe release of these cytokines byBronchial asthmaBronchial asthmaoccurs as an intrinsic and an extrinsic, atopy-relatedform. Although different immunological pathomech-form. Although different immunological pathomech-mon an eosinophil-dominated bronchial inflammatoryreaction of the bronchial tissue [308, 411Ð417]. Eosino-aged epithelium and mucous plugs [80, 308, 351, 352,418, 419]. An increase in the number of bronchial epithe-418, 419]. An increase in the number of bronchial epithe-Immunohistological analysis of bronchial tissue hasprovided additional evidence that eosinophils are active-ly involved in the inflammatory tissue reaction in asth-matic airways [308, 352, 418]. Histological sections ofmatic airways [308, 352, 418]. Histological sections ofImmunofluorescence studies with two mouse mono-clonal antibodies EG1 (specific for ECP) and EG2(specific for a common epitope of secreted ECP andthe basement membrane and among epithelial cells, from asthmatic subjects [352, 420Ð423]. In addition, anand the degree of bronchial hyperresponsiveness expressed[420, 424, 425] has been reported. A correlation wasalso found between the number of blood eosinophils andalso found between the number of blood eosinophils andmatics with the late allergic response [426].

Moreover,bronchial hyperresponsiveness [354]. In untreated patients,season, but this did not occur in patients receivingseason, but this did not occur in patients receiving427Ð429]. Compact clusters of columnar cells contain-as Creola bodies may also be seen [416]. In addition,of this protein is specific for asthma [329, 428]. Theof this protein is specific for asthma [329, 428]. TheIncreased numbers of eosinophils are also found inBAL fluid from asthmatics [310, 352, 417, 430Ð435].In stable, nonsymptomatic asthmatics or in cortico-however, is not excessively increased, and may even benormal [433, 436]. In addition, eosinophil count maythma. Fordemonstrated that the blood eosinophil count may beeEosinophil-derived basic proteins have been shown tocause direct damage to both guinea-pig and humanrespiratory epithelium [351]. At low doses, MBP caus-iary beating. At higher concentrations, MBP detachesexposing the basal cell layer. At an ultrastructural level,cellular contents [253, 325, 351, 416, 438]. Examin-the sites of epithelial damage [351]. ECP also caused aas assessed by inverted microscopy. In addition, EPO KROEGELETAL the eosinophil represents an effector cell in asthmaand development of airway inflammation. With thestudies have shown that local endobronchial allergenurally occurring asthma (for review see [436]). Theseabsence of provocation. In addition, when mild asth-observed after 19Ð96 h [43, 138, 153, 432, 436]. Thisnumbers of eosinophils. There was a less pronouncednumbers of eosinophils. There was a less pronounced37, 43, 138, 153, 163, 432, 436]. In contrast, no changemin after challenge. The results clearly demonstratetumour of the neck [439]. Since then, a number of re-malignancies, lymphocytic leukaemias, intestinal tu-malignancies, lymphocytic leukaemias, intestinal tu-)However, expression of eosinophilia both in peripheralblood and tumour tissue varies significantly, and onlya small proportion of patients with oral, gastric andbreast carcinomas show increased eosinophils within thetumour tissue. In contrast, in both carcinoma of thetumour tissue. In contrast, in both carcinoma of theapproximately one third of the cases. Even more impor-approximately one third of the cases. Even more impor-In lung cancer, only a few studies have been publishedto date. In a study of 72 operable primary lung cancers,to date. In a

study of 72 operable primary lung cancers,eosinophils. Follow-up studies indicated that eosinophiloutcome [441, 442]. In a recent prospective study on of the lung [443]. Since ECP is a better indicator ofbronchogenic tumours. Whether ECP or other eosinophil-the host. As mentioned above, eosinophil-derived pro-the host. As mentioned above, eosinophil-derived pro-350]. In addition, tumour patients which responded350]. In addition, tumour patients which responded445] showed double the median survival of those who445] showed double the median survival of those whomammary tumours in mice was reduced when theydeveloped an eosinophilia following infection withTrichinella spiralis[446]. Furthermore, developmentmour inoculation [447]. When tumour cells secretingthan in animals with nonsecreting tumours [288]. Inophils. Thus, it may be concluded that eosinophils maycontribute to the host antitumour response. Further8). However, the increased knowledge of eosinophilmatory action, immune response modifiers, anticytokinetors, antioxidants and protein neutralizers. The finaleosinophil-related disorders. Corticosteroids are likelydistal effector functions of eosinophils. For instance, PULMONARYIMMUNECELLSEOSINOPHILLEUCOCYTE peripheral blood eosinophils [152, 410, 449Ð451], pre-peripheral blood eosinophils [152, 410, 449Ð451], pre-and inhibition of eosinophil tissue infiltration probablyby inhibiting both eosinophil chemotaxis by inhibiting both eosinophil chemotaxis adherence to endothelium [47, 457Ð459]. Corticost-cytotoxicity [460]. In asthmatics, inhaled steroids reducecytotoxicity [460]. In asthmatics, inhaled steroids reduce424, 461, 462], as well as in BAL fluid [463]. In ad-424, 461, 462], as well as in BAL fluid [463]. In ad-which may be due, in part, to inhibition of GM-CSFproduction by bronchial epithelial cells [292, 293]. Ste-production by bronchial epithelial cells [292, 293]. Ste-superoxide anions by eosinophils when administered tonormal subjects [465].In addition, steroids have been shown to inhibit eosin-ophil activation in vitro.Several studies have demon-strated that corticosteroids prevented the expression ofFc receptors [466], degranulation [467], chemotaxis andadherence [456, 457], the formation of lyso-PAF,leukotrienes, and 15-hydroxyeicosatetraenoic acid (15-HETE) [468], and the release of EPO and superoxideanions [469].Eosi

nophils express glucosteroid receptors [470], andin one report their absence was correlated with clinicalglucosteroid resistance in the hypereosinophilic synd-rome [471].-agonists.2-agonists are the most effective bron-chodilators in current use, and act predominantly by re-laxing airway smooth muscle, but also by inhibitingmast cell degranulation [472]. In passively sensitizedchallenge [473]. In humans, treatment with challenge [473]. In humans, treatment with Furthermore, 2-agonists reduced the release of bothEPO and superoxide anions from zymosan stimulatedhuman eosinophils in vitro[474]. The effect of these[474]. The effect of these476]. It is interesting that the magnitude of inhibitionXanthines, such as theophylline, are bronchodilatingdrugs in the management of asthma. Although it hasdrugs in the management of asthma. Although it hasphil function is yet to be established. Purified guinea-the cells stimulated with opsonized zymosan. Only highM) were inhibitory [475]. This Previous studies have established that guinea-pigperitoneal eosinophils contain at least one type IV phos-phodiesterase (PDE) isoenzyme [479, 480]. In an ani-phodiesterase (PDE) isoenzyme [479, 480]. In an ani-the influx of eosinophils in the peritoneum followingserum-protein challenge [482]. In addition, eosinophilsasthmatic subjects. DSCG treatment significantly re-BAL fluid [417]. In addition, it has been shown to KROEGELETAL Table 8. Ð Effects of various drugs on cellular functionsEosinophil function Anti-eosinophil drugTissue infiltrationCorticosteroidsChemotaxisCorticosteroidsSurface receptor expressionCorticosteroidsAdhesionCorticosteroidsHypodensityCorticosteroidsSurvivalCorticosteroidsGranular protein secretionCorticosteroidsOxygen radical productionCorticosteroidsLipid mediator releaseCorticosteroidsCytotoxicityCorticosteroids the late response to allergen in IgE-sensitized rabbits[483], and to PAF in guinea-pig [484] and human skin[483], and to PAF in guinea-pig [484] and human skinin vitro[486,487].Nedocromil sodium.Nedocromil sodium is a pyra-noquinoline dicarboxyline acid which has been demon-strated to have some beneficial effects in various modelsof asthma, including human airway response to hyper-osmolar challenge [488], PAF-mediated bronchocon-striction [489], early and late responses to allergenchallenge in asthmatics [490, 491], and eosin

ophil re-cruitment in humans [491]. Besides its inhibitory actionon mast cells, neutrophils, monocytes and platelets[492Ð496], nedocromil sodium has been shown to block[492Ð496], nedocromil sodium has been shown to block499], surface antigen expression [500], leukotriene C4secretion in response to various agents [499, 501] aswell as density change, damage to airway epithelium[502, 503] and other cytotoxic mechanisms [498, 500].models [504]. Besides its abili-models [504]. Besides its abili-the airways that results from exposure to PAF [506].Cetirizine.Cetirizine is a second generation, non-ment of asthma [507Ð510]. In addition to its anti-ment of asthma [507Ð510]. In addition to its anti-514]. For instance, cetirizine has been shown to inhib-[512, 513, 515], and[512, 513, 515], andplement expression and cytotoxicity [516], preventsIL-5-induced ICAM-1 expression in vitro[517], andselectively blocks adhesion of eosinophil to endothelialcells [518] possibly viathe very late activation anti-gen-4 (VLA-4)/vascular cell adhesion molecule-1(VCAM-1) interaction.Azelastine.Azelastine is a phthalazinone derivativewith anti-allergic and anti-asthmatic properties [504].Besides its potent antihistamine action, it also hasinhibitory effects on oxygen radicals released by neu-trophils, macrophages, and eosinophils [519]. How- Their potent inhibitory effect on eosinophil function[64, 72, 194] and in antigen-induced airway responses in humans [521Ð525]. How-induced airway responses in humans [521Ð525]. How-The reasons for this discrepancy are currently not un-derstood. However, several explanations may be con-sidered. Firstly, it may prove difficult to effectivelycrine" effect influencing only neighbouring cells. Itcurrently available competitive antagonists. Perhaps,than choline. Different molecular species of PAF canbe produced by an inflammatory cell. The biologicalsignificance of the molecular heterogeneity is not yetclear. However, given the variable biological activityclear. However, given the variable biological activitymatory cell may be able to alter the predominant "type"of PAF, thereby determining the degree of inflam-matory activity. Furthermore, PAF may use not onlydifferent molecular species with different biologicalaffinity states and different signalling mechanisms tothma [531]. Hence,block total PAF activity. More potent PAF receptor

block total PAF activity. More potent PAF receptorLeukotriene synthesis inhibitors and receptor antago-nists.Sulphidopeptide leukotrienes (LT) had alreadybeen identified in the late 1930s by Kellewy andTrethewie, and have since been suggested as playing arole in allergic airway disease by mediating smoothmuscle contraction, bronchial secretion of mucus, andairway mucosal oedema by increasing postcapillaryvenopermeability [533, 534]. In addition, a recentrecruitment in human airways [535]. Sulphidopeptideleukotrienes, LTC[536]. Eosinophils are a major source for LTC PULMONARYIMMUNECELLSEOSINOPHILLEUCOCYTE The development of the leukotriene D receptor antag-onists has confirmed the relative contribution of thesespecific cellular products in allergic disease, such asasthma. Indeed, clinical and experimental studies em-ploying several LTDreceptor antagonists suggest areceptor antagonists suggest ainduced asthma [546], PAF or antigen-mediated bron-choconstriction [547Ð549], as well as Ascaris-inducedlate-phase bronchoconstriction, airway responsiveness,microvascular leakage, and leucocyte infiltration [550,551]. However, since binding sites for sulphidopeptideeosinophils [63, 119]. The eicosanoids mediate theirmuscle. Hence, conceptually thromboxane receptorantagonists, such as GR32191 or ICI 92605 may bewhich do not prevent synthesis of PGD. While. WhileCytokine antagonists and cyclosporin.Since cyto-kines may play a crucial role in mediating eosinophiltissue infiltration, the administration of cytokine antag-onists may be useful in eosinophil-associated disease.This view is supported by animal experiments showingthat monoclonal anti-IL-5 antibodies suppress bloodeosinophilia and infiltration of eosinophils into the lungsof mice parasitized with Nippostrongylus brasiliensis[367, 553, 554]. In view of the capacity of GM-CSF to[367, 553, 554]. In view of the capacity of GM-CSF towith a cytokine receptor blocker may augment theireffectiveness.A similar approach to modifying the elaboration ofeosinophilopoietic cytokines may be achieved by otherdrugs, such as cyclosporin A. Cyclosporin A has beentransplantation. It is thought to inhibit proliferation oftransplantation. It is thought to inhibit proliferation ofalso affect immune effector cells, such as mast cells,basophils or eosinophils viainteraction with cycloph-ylin [557]; and unpublished results.

In an experimentalit could be demonstrated that cyclosporin A inducedacytokines [558]. In a clinical randomized cross-over A improved the lung function and reduced the numberof exacerbations in the asthmatics. Although its modeepithelium toxicity [253, 330]. Hence, detoxificationto prevent inflammatory tissue damage. N-acetyl-L-act as an ing agent. Thus, it may neutralize toxic oxygenradicals and other oxidative mediators of inflreleased by eosinophils and other immune cells. How-matory conditions is uncertain [560Ð562], and awaitsAs has been mentioned above, heparin and relatedous cells [252Ð254]. Hence, administration of theway epithelium. In an animal model, heparin reducedway epithelium. In an animal model, heparin reduced253]. In addition, heparin has been shown to inhibit253]. In addition, heparin has been shown to inhibitphocyte activation [564] endothelial permeability [565],and negative charge [566], or vianeutralization of eosinophil[567]. Finally, heparin may[567]. Finally, heparin mayA similar, yet more experimental, approach to neu-tralize basic proteins employing other acidic substanceshas only recently been suggested. For instance, acidictracheal epithelium [332, 333]. In addition, aerosol in-accelerating. So far, several aspects of the immuno-biology of the eosinophil have been outlined. Theseduction, the role of cytokines on eosinophil differen- KROEGELETAL tissues. However, numerous important questionsto be addressed. Whilst most of the current knowledgediseases, such as eosinophilic pneumonia,vascugranulomatous disorders and even malignancies. It mayponse by raising eosinophil cytotoxicity. In addition, thekines or other proteins has to be further elucidated.Thegeneral reaction of inflammatory cells following acti-vation deserves further attention. Work on the nature ofportant perspective. In this context, understanding ofeosinophil tissue infiltration. However, other factorsvation. Finally, a number of drugs with potential anti-eosinophil properties have been developed. Studies arein the context of eosinophil-dominated diseases. There323.Butterworth AE, Wasso DL, Gleich GJ, Loegering DA,David JR. Damage to schistosomula of 324.McLare DJ, McKean JR, Olsson I, Venge P, Kay AB.Steinmuller D. Cytotoxic properties of the eosinophil326.Davis WB, Fells GA, Sun XH, Gadek JE, Venet A,Crystal RG. Eosinophil-mediated

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