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PubMed1996

Expression and function of the Fas receptor on human blood and tissue eosinophils.

The interaction between activated T cells and eosinophils has been proposed to play an important role in the pathogenesis of allergic diseases. T cell-derived cytokines such as interleukin-5 and granulocyte/macrophage colony-stimulating factor inhibit eosinophil apoptosis and may therefore contribute to the development of tissue and blood eosinophilia in these disorders. Withdrawal of these cytokines leads to eosinophil apoptosis in vitro. In contrast, the mechanisms which actively induce apoptosis in eosinophils are at present not completely understood. In this study, we demonstrate that freshly isolated human eosinophils express mRNA and protein for the Fas receptor. Using anti-Fas monoclonal antibody (mAb), we show that Fas activation accelerates apoptotic eosinophil death in vitro. Moreover, treatment of nasal polyps ex vivo with anti-Fas mAb decreased eosinophilic tissue inflammation. However, we observed that blood as well as tissue eosinophils derived from some eosinophilic donors do not express functional Fas receptors, although Fas protein is normally expressed in these cells. This implies that the susceptibility of the Fas receptor is a matter of regulation in eosinophils as previously observed in other systems. These data suggest that Fas ligand/Fas interactions are involved in the regulation of eosinophil apoptosis and that defects in this system could contribute to the accumulation of these cells in allergic and asthmatic diseases.

Antibodies, Monoclonal↗
PubMed1997

The CC chemokine antagonist Met-RANTES inhibits eosinophil effector functions through the chemokine receptors CCR1 and CCR3.

Eosinophils are predominant effector cells not only in allergic diseases but also in connective tissue diseases. The recruitment of eosinophils to the site of inflammation and release of reactive oxygen species leading to tissue damage and propagation of the inflammatory response are mediated by chemokines. Thus, agents that would be able to inhibit or antagonize chemokine-induced eosinophil activation are interesting as therapeutical agents. We describe the effect of a chemokine receptor antagonist, Met-RANTES, on human eosinophil effector functions in response to RANTES, monocyte chemoattractant protein (MCP)-3 and eotaxin. Met-RANTES was able to inhibit dose-dependently [Ca2+]i transients in eosinophils following stimulation with RANTES, MCP-3 and eotaxin. Whereas maximal and half-maximal inhibitory effect of Met-RANTES following stimulation with RANTES and MCP-3 were observed at 2 micrograms/ml and 1 microgram/ml, respectively, maximal and half-maximal inhibitory effects of Met-RANTES in response to eotaxin were detected at 10 micrograms/ml and 3 micrograms/ml. Moreover, eotaxin-induced [Ca2+]i transients were only half reduced at a Met-RANTES concentration at which RANTES and MCP-3 were completely blocked. Besides its effect on [Ca2+]i transients, Met-RANTES dose-dependently inhibited actin polymerization in eosinophils following chemokine stimulation. Whereas Met-RANTES totally inhibited RANTES- and MCP-3-induced actin polymerization at 5 micrograms/ml, the eotaxin-induced response was only reduced by 50%. However, Met-RANTES inhibited dose-dependently the release of reactive oxygen species in response to RANTES, MCP-3 and eotaxin. Again, eotaxin-induced release of reactive oxygen species, however, was only half reduced at a Met-RANTES concentration (10 micrograms/ml) at which RANTES and MCP-3 were completely blocked. The results of this study show that (1) Met-RANTES is an effective and powerful antagonist of effector functions of human eosinophils following stimulation with RANTES, MCP-3 and eotaxin; (2) Met-RANTES seems to be able to antagonize the response of eosinophils through chemokine receptor 1 (CCR1) preferentially to CCR3; (3) Met-RANTES antagonizes eosinophil but not neutrophil effector functions and might be therefore of interest for a new therapeutical approach to prevent the invasion and destructive power of eosinophils in diseases that are accompanied by eosinophil infiltration such as allergic asthma and connective tissue diseases.

Actins↗
PubMed1997

Eosinophils inhibit retroviral transduction of human target cells by a ribonuclease-dependent mechanism.

Human eosinophils contain a number of granule proteins for which specific physiological roles remain unclear. The combined ribonucleolytic and membrane disruptive properties of the eosinophil-derived neurotoxin and eosinophil cationic protein, respectively, suggest the possibility that eosinophils might participate in host defense against enveloped single-stranded RNA viruses. To test this hypothesis, stocks of a replication-defective retrovirus encoding the reporter gene beta-galactosidase were pretreated with isolated human eosinophils, then used to transduce human erythroleukemia (K-562) target cells. Histochemical staining for beta-galactosidase activity was used to detect and quantitate the transduced cells. Co-incubation of retrovirus with eosinophils (0.4 x 10[6]/mL) before target cell transduction resulted in a marked decrease in transduction efficiency corresponding to an approximately 20-fold dilution of viral stock (P < 0.01), an effect that was directly proportional to the concentration of eosinophils, and that was reversed in the presence of ribonuclease inhibitor. Reverse transcriptase-polymerase chain reaction analysis demonstrated loss of the retroviral RNA genome as a result of eosinophil pretreatment, indicating that eosinophils are capable of mediating direct ribonucleolytic destruction of the isolated retroviral particles. Our results demonstrate that eosinophils function as effective anti-retroviral agents in vitro via the actions of their secreted ribonucleases, and suggest that eosinophils may represent an unrecognized arm of host defense against enveloped single-stranded RNA viral pathogens.

Eosinophils↗
PubMed1991

Eosinophil infiltration and degranulation in Helicobacter pylori-associated chronic gastritis.

Eosinophil granules contain cationic proteins, including the major basic protein, which are toxic to mammalian tissue. While eosinophils have been observed to comprise part of the inflammatory reaction in acute Helicobacter pylori gastritis, the role of the eosinophil in the pathogenesis of chronic gastritis is unknown. We evaluated whether eosinophil infiltration and degranulation are associated with chronic gastritis and H. pylori infection. We studied eight patients with chronic H. pylori antral gastritis, three with chronic antral gastritis in the absence of H. pylori, 11 healthy age-matched volunteers without antral gastritis, and eight patients with H. pylori-negative chronic specific gastritis (three Crohn's antral gastritis and five Ménétrier's disease). Serial sections were stained with hematoxylin and eosin, with Giemsa, and by a specific indirect immunofluorescence technique for eosinophil granule major basic protein. Specimens were graded independently by three observers and scores of 0-3 were given for eosinophil infiltration and degranulation (0 = none to 3 = confluent infiltration and/or degranulation). In H. pylori antral gastritis, significantly greater eosinophil infiltration and degranulation were found compared to the normal group, Ménétrier's disease, and chronic H. pylori-negative gastritis. There was no significant difference between gastric Crohn's disease and H. pylori gastritis. The severity of chronic gastritis was significantly correlated with the eosinophil score. Eosinophil degranulation did not appear to be greater at or near sites of bacterial colonization in the H. pylori gastritis specimens. The results suggest that eosinophil infiltration and degranulation may be associated with H. pylori gastritis. We postulate that the release of toxic cationic proteins from eosinophils contributes to the inflammatory changes present in H. pylori gastritis.

Cell Degranulation↗
PubMed2001

Evaluation of the expression of NADPH oxidase components during maturation of HL-60 clone 15 cells to eosinophilic lineage.

OBJECTIVE: Superoxide-generating NADPH oxidase consists of the membrane-bound cytochrome b558 (gp91phox and p22Phox) and the cytosolic components (p67phox, p47phox, p40phox and rac). In this study, we evaluated the superoxide-generating activity and the expression of NADPH oxidase components during eosinophilic maturation using HL-60 clone 15 cell line. MATERIALS AND METHODS: HL-60 clone 15 cells were matured to eosinophils by incubation with 0.5 mM butyrate for 7 days, and NADPH oxidase components were detected by Northern blot, Western blot analyses and immunocytochemical staining. Moreover, superoxide-generating activity was examined by nitro blue tetrazolium (NBT) assay. RESULTS: Northern blot and Western blot analyses revealed that mRNAs and proteins for gp91phox, p67phox and p47phox were expressed after eosinophilic myelocyte stages, whereas mRNAs and proteins for p40phox and rac-2 were expressed from the promyelocyte stage. Interestingly, p22phox mRNA was expressed from the promyelocyte stage, but its protein was expressed after eosinophilic myelocyte stages. Consistent with the results of Western blotting, immunocytochemical staining of butyrate-induced HL-60 clone 15 cells indicated that gp91phox, p22phox, p67phox and p47phox were detected after eosinophilic myelocyte stages (eosinophilic myelocytes, eosinophilic metamyelocytes, eosinophilic band cells and eosinophilic-segmented cells), whereas p40phox and rac-2 were expressed from the promyelocyte stage. Moreover, almost the same results as those with butyrate-treated HL-60 clone 15 cells were obtained using human bone marrow cells by immunocytochemical staining. Furthermore, nitro blue tetrazolium (NBT) assay indicated that superoxide could be produced after eosinophilic myelocyte stages but not produced before the promyelocyte stage. CONCLUSIONS: Together these observations indicate that all the components for NADPH oxidase are expressed, and the superoxide-producing activity is obtained after myelocyte stages during eosinophilic maturation.

Amino Acid Sequence↗
PubMed2006

The role of mast cells and eosinophils in chronic gastritis.

The role of mast cells and eosinophils in influencing the pathology of chronic gastritis remains unclear. We attempted to study the relationship between endoscopy and the mast cell and eosinophil infiltrate. We also studied the role of gene polymorphisms, Helicobacter pylori density and the CagA antibody status in influencing the mast cell and eosinophil infiltrate. One hundred and twenty consecutive patients were studied. Endoscopic evaluation was done and 3 antral biopsies were taken from each patient and were assessed for eosinophilic and mast cell infiltration, H. pylori density and the density of the other inflammatory cells as per the revised Sydney system. Cytokine gene polymorphisms (IL-1beta, IL-1RA and TNF-alpha) were done on the DNA extracted from the peripheral blood by PCR-RFLP. ELISA was done on the patients' serum for the anti-CagA antibody titres. Nodularity is strongly associated with the presence and density of eosinophils on biopsy (P < 0.05). Eosinophil density is strongly associated with the density of H. pylori, neutrophils, lymphocytes, plasma cells, atrophy, ulceration, foveolitis and lymphoid follicles. The mast cell density is not associated with any of the other histopathological variables. Gene polymorphisms and the CagA antibody titres have no relationship to the mast cell and eosinophil density. Eighty-one patients showed positive anti-CagA antibody titres but there was no association with the eosinophilic or the mast cell infiltrate. It is likely that eosinophilic infiltration is influenced by the H. pylori density but the CagA protein has no role to play in influencing the grade of the eosinophilic infiltrate in the Indian context. Cytokine gene proinflammatory polymorphisms have no role to play in influencing the eosinophilic or the mast cell response. It is likely that other mediators are involved in the inflammatory cell responses.

Adolescent↗
PubMed1995

Human eosinophils migrate across an intestinal epithelium in response to platelet-activating factor.

BACKGROUND/AIMS: Transmigration of eosinophils across intestinal epithelia occurs in a variety of mucosal inflammatory disorders and results in the formation of crypt abscesses containing eosinophils. However, the conditions required to drive transepithelial migration of eosinophils are not understood. METHODS: This study investigated eosinophil migration across intestinal epithelia using purified eosinophils and confluent monolayers of the human intestinal epithelial cell line T84. RESULTS: Unactivated eosinophils (i.e., no granulocyte/macrophage colony-stimulating factor [GM-CSF] preexposure) did not migrate across T84 monolayers in the presence of transepithelial gradients of C5a, n-formyl-methionyl-leucyl-phenylalanine (fMLP), or platelet-activating factor (PAF). In contrast, activation of eosinophils by coincubation or pretreatment with GM-CSF enabled transepithelial migration in response to PAF but not to C5a or fMLP gradients in a time- and dose-dependent fashion. Specificity was confirmed by both the PAF receptor antagonist WEB-2086 and the PAF enantiomer 2-lyso-beta-acetyl-gamma-O-hexadecyl. Finally, addition of functionally inhibitory monoclonal antibodies to CD11b but not CD11a, very late activation antigen (VLA-4), or intracellular adhesion molecule 1 inhibited eosinophil migration. CONCLUSIONS: These studies establish that physiologically directed migration of eosinophils across model epithelia occurs but that this process is governed by the state of eosinophil activation, the specific chemotactic gradient imposed, and the availability of specific surface integrins to participate in putative eosinophil-epithelial adhesion steps.

Adult↗
PubMed1994

Measurement of neutrophil and eosinophil adhesion to E-selectin, VCAM-1, and ICAM-1 by the use of transfected fibroblast cell lines.

A method which enables the specific measurement of neutrophil and eosinophil adhesion to the endothelial cell adherence receptors E-selectin, VCAM-1 and ICAM-1 has been developed. The method is based on continuous cultures of cell lines of transfected hamster kidney fibroblasts (BHK-21), that selectively express each of the endothelial cell adhesions molecules. Isolated granulocytes are added to the cultured adherent fibroblasts at a ratio of 20:1 and the cells are coincubated for 60 min at 37 degrees C. After removal of the nonadherent granulocytes the amount of adherent granulocytes could be measured by addition of detergent and a peroxidase substrate. Selective measurement of neutrophil and eosinophil adhesion was accomplished by addition of detergent to the adherent cells, collection of extracts followed by measurement of the concentration of an eosinophil (eosinophil cationic protein) and a neutrophil (myeloperoxidase) granule protein, respectively, in the extracts. At basal conditions neutrophils and eosinophils showed significant adhesion to E-selectin and eosinophils a low degree of adhesion to VCAM-1. Significant adhesion of neutrophils and eosinophils to ICAM-1 and of eosinophils to VCAM-1 was selectively induced by addition of manganese ions (Mn2+) at a concentration of 0.5 mmol/l. Neutrophils demonstrated a significantly higher adhesion to E-selectin than eosinophils, while eosinophil adhesion to ICAM-I was significantly higher than that of neutrophils. In conclusion, a method to compare the adhesive capacity of neutrophil and eosinophil granulocytes towards specific endothelial cell adhesion molecules has been developed.

Animals↗
PubMedDate not supplied

Eosinophilia and eosinophil helminthotoxicity in patients treated for Schistosoma mansoni infections.

The changes in eosinophil levels and in eosinophil-mediated antibody-dependent schistosomular cytotoxicity, following treatment for Schistosoma mansoni infections, have been investigated in 2 similar groups of patients aged 15-50 years. Patients in group 1 were treated with either hycanthone or oxamniquine, and those in group 2 with hycanthone or praziquantel. Eosinophil levels were significantly increased in both groups. In group 1 peripheral blood eosinophil counts rose from a mean of 175/microliters before treatment to 745/microliters 3 weeks after treatment, and in group 2 from 181/microliters to 1066/microliters. The increase in eosinophil levels was positively correlated with a rise in circulating anti-adult worm antibodies (r = -0.587, P less than 0.05), whereas a negative correlation was recorded with anti-egg antibodies (r = -0.727). Despite some enhanced eosinophil helminthotoxicity following treatment in some of the individuals in group 1 (7/15), the change overall was not significant. In group 2, in which a different standard anti-schistosomular antibody was used, the eosinophil killing capacity recorded at 3 weeks was lower than that before commencement of treatment (t = 2.89, P less than 0.01). The eosinophil stimulating activity, detected in cultured mononuclear cell supernatants (MCS) from individual patients, correlated with eosinophil levels (r = 0.582, P less than 0.02) but there was no association with eosinophil killing. MCS activity did not appear to be boosted by treatment. These studies showed that peripheral blood eosinophil counts were increased following treatment, but their ability to kill schistosome larvae is variable and may depend on the immune serum used as the source of anti-schistosomular antibody.

Adolescent↗
PubMed1988

Stimulus-dependent differences in superoxide anion generation by normal human eosinophils and neutrophils.

The role of eosinophils in allergic and hypersensitivity diseases has yet to be fully established and remains limited by techniques to isolate the eosinophil in high purity. Consequently, most studies that evaluate and characterize eosinophil function are conducted with isolates from patients with hypereosinophilia. There is, however, evidence to suggest that isolates from such patients do not represent normal function. Now, with new techniques to isolate and purify eosinophils from normal subjects without eosinophilia, metabolic function of the normal eosinophil can be assessed. To accomplish this, granulocytes from healthy volunteers were separated by continuous density Percoll gradients into populations of purified eosinophils (90.3 +/- 1.9%) and neutrophils (98.2 +/- 0.4%). Superoxide (O2-) generation was measured with a microassay of superoxide dismutase-inhibitable cytochrome c reduction in response to several soluble and particulate agonists. Normal eosinophils generated significantly more O2- in response to either phorbol myristate acetate or calcium ionophore A23187 than their matched neutrophil fractions. In contrast, differences in granulocyte response to zymosan and chemotactic peptide, N-formyl-methionyl-leucyl-phenylalanine, were dependent on the presence of cytochalasin B (CB) in the reaction. N-formyl-methionyl-leucyl-phenylalanine-stimulated eosinophils generated less O2- in the absence of CB but similar amounts in the presence of CB, compared to neutrophils. Activation by zymosan in the presence of 10% autologous serum generated similar amounts of O2- in all the cell populations when CB was present; however, in the absence of CB, neutrophils produced less O2- when they were compared to eosinophils. Therefore, normal eosinophils respond differently to some activators, compared to neutrophils, and these differences may prove significant as the contribution of eosinophils to inflammation becomes established.

Adolescent↗
PubMed1988

Release of lysosomal enzyme beta-glucuronidase from isolated human eosinophils.

The human eosinophil contains lysosomal enzymes that can contribute directly to tissue injury and inflammation. Characterization of lysosomal-enzyme release from the eosinophil has been largely limited to isolates from patients with hypereosinophilia. Because eosinophils from such individuals may not demonstrate normal functional responses, we established a method to obtain purified, normal human eosinophils with a Percoll gradient. With this method, it is possible to isolate eosinophils (95.5 +/- 3.9%) and neutrophils (greater than 99%) in high purity from normal subjects. With these granulocyte isolates, we evaluated and compared release of the lysosomal enzyme, beta-glucuronidase (BG), after cell activation with opsonized zymosan particles. Neutrophils released 33.0 +/- 1.2% (mean +/- SEM; n = 5) of total BG (30 minutes of incubation with zymosan), whereas eosinophil secretion was 24.2 +/- 1.7% (n = 5). The fungal metabolite, cytochalasin B (CB), which inhibits microfilament activity, enhanced BG secretion from neutrophils (33.0 +/- 1.2% to 42.8 +/- 2.8% with CB; p less than 0.01). In contrast, CB had no effect on eosinophil BG release. Interestingly, BG content in eosinophils is 101.2 +/- 3.9 micrograms phenolphthalein per 10(6) cells per 18 hours, which compares to a neutrophil level of 51.0 +/- 3.2 (p less than 0.001). Thus, although eosinophils and neutrophils release a similar percentage of total cellular BG on stimulation with zymosan particles, the absolute amount of enzyme per cell is greater in the eosinophil than in the neutrophil. Study of eosinophil function promises to elicit a more complete insight into its contribution to tissue injury.

Cell Separation↗
PubMed1991

A current perspective on the role of eosinophils in dermatologic diseases.

Eosinophils are frequently observed in cutaneous inflammation, but little is known of their significance in the pathophysiology of cutaneous disease. Recent studies of the structure, content, and activities of the eosinophil have shown that it has potent toxic proteins with the potential to mediate tissue damage. Furthermore, immunofluorescent localization of eosinophil granule proteins has shown that eosinophils disrupt in tissue and deposit toxic granule proteins. The deposition of granule proteins in several diseases is vastly out proportion to the number of identifiable cells and indicates that eosinophil involvement in cutaneous disease cannot be judged by the number of intact eosinophils in the tissue. Specifically, deposition of eosinophil granule proteins outside of eosinophils has been observed in eczematous lichenified disorders with elevated serum levels of immunoglobulin E, in urticarial and angioedematous disorders, and in bullous diseases. The structural, compositional, and functional characteristics of eosinophils are reviewed, and evidence of eosinophil degranulation in cutaneous diseases is presented. Mechanisms whereby eosinophil degranulation may mediate pathophysiologic effects are also discussed.

Asthma↗
PubMed2005

Human peripheral blood eosinophils induce angiogenesis.

Eosinophils play a crucial role in allergic reactions and asthma. They are also involved in responses against parasites, in autoimmune and neoplastic diseases, and in fibroses. There is increasing evidence that angiogenesis plays an important role in these processes. Since eosinophils are known to produce angiogenic mediators, we have hypothesized a direct contribution of these cells to angiogenesis. The effect of human peripheral blood eosinophil sonicates on rat aortic endothelial cell proliferation (in vitro), rat aorta sprouting (ex vivo) and angiogenesis in the chick embryo chorioallantoic membrane (in vivo) have been investigated. To determine whether eosinophil-derived vascular endothelial growth factor influences the eosinophil pro-angiogenic activity, eosinophil sonicates were incubated with anti-vascular endothelial growth factor antibodies and then added to the chorioallantoic membrane. Vascular endothelial growth factor mRNA expression and vascular endothelial growth factor receptor density on the endothelial cells were also evaluated. Eosinophils were found to enhance endothelial cell proliferation and to induce a strong angiogenic response both in the aorta rings and in the chorioallantoic membrane assays. Pre-incubation of eosinophil sonicates with anti-vascular endothelial growth factor antibodies partially reduced the angiogenic response of these cells in the chorioallantoic membrane. Eosinophils also increased vascular endothelial growth factor mRNA production on endothelial cells. Eosinophils are able to induce angiogenesis and this effect is partially mediated by their pre-formed vascular endothelial growth factor. This strongly suggests an important role of eosinophils in angiogenesis-associated diseases such as asthma.

Animals↗
PubMed2004

Expression and function of the angiopoietin receptor Tie-2 in human eosinophils.

BACKGROUND: Increased vascularity of bronchial mucosa is closely related to the expression of angiogenic factors, which contribute to the pathogenesis of diseases such as asthma bronchiale. OBJECTIVE: Here we examine the effects of the angiogenic growth factors angiopoietin 1 and angiopoietin 2 on eosinophil function in vitro and possible involvement of the angiopoietin receptor Tie-2. METHODS: Eosinophil migration was studied by micropore filter assays. Signaling mechanisms required for angiopoietin-dependent migration were tested by using signaling enzyme blockers. Tie-2 mRNA and receptor expression on the cell surface of eosinophils was demonstrated in RT-PCR and by fluorescence-activated cell sorting analysis. RESULTS: Angiopoietin 1 significantly stimulated eosinophil chemotaxis via activation of phosphodiesterase, phosphatidylinositol 3'-kinase, and tyrosine kinases. The effect on eosinophil migration of angiopoietin 1 was reversed by an antibody against the Tie-2 receptor and by angiopoietin 2. Incubation of eosinophils with angiopoietin 1 abolished the chemotactic effects of vascular endothelial growth factor on human eosinophils via the Tie-2 receptor. Finally, Tie-2 expression by human eosinophils was demonstrated on the transcriptional and protein level. CONCLUSIONS: Data suggest that angiopoietin 1 stimulates directed migration and possibly inhibits vascular endothelial growth factor-induced eosinophil chemotaxis via its Tie-2 receptor, which is expressed by eosinophils. Thus, angiopoietin 1 may play an important role in the modulation of eosinophilic inflammation.

1-Methyl-3-isobutylxanthine↗
PubMed2004

Migration and accumulation of eosinophils toward regional lymph nodes after airway allergen challenge.

BACKGROUND: Eosinophils play a major role in allergic airway inflammation because of their ability to release toxic mediators. In addition, they are able to migrate toward draining thoracic lymph nodes (TLNs) after intratracheal administration, where they can function as antigen-presenting cells. OBJECTIVE: In this study, we evaluated in vivo eosinophil migration toward the TLN after allergen sensitization and analyzed expression of molecules involved in antigen presentation. METHODS: Mice were sensitized by intraperitoneal injection of ovalbumin on days 1 and 10 and challenged once intranasally with ovalbumin on day 20. The kinetics of eosinophilia was evaluated in blood, lung tissue homogenate, bronchoalveolar lavage fluid, and TLN. Cell surface staining was analyzed by flow cytometry. RESULTS: The kinetics of eosinophil recruitment was similar in TLN, lung tissue, and blood, beginning at 12 hours and peaking at 48 hours after allergen challenge. Approximately 70% of TLN eosinophils expressed MHC class II molecules, compared with less than 25% in blood and lungs. Moreover, TLN eosinophils expressed higher levels of MHC class II and CD86 compared with blood and lung eosinophils. Most eosinophils expressed CD80 and CD54, whereas only a few eosinophils expressed CD40. Eosinophils in lungs and TLN appeared to be activated with lower CD62-ligand expression compared with blood eosinophils. CONCLUSION: The presence of eosinophils with a different phenotype in the TLN at early time points after allergen challenge of sensitized mice supports their capacity to serve as antigen-presenting cells, sustaining allergic/inflammatory responses in the airways.

Administration, Inhalation↗
PubMed2004

Rebound eosinophilia after treatment of hypereosinophilic syndrome and eosinophilic gastroenteritis with monoclonal anti-IL-5 antibody SCH55700.

BACKGROUND: Hypereosinophilic syndrome and eosinophilic gastroenteritis with peripheral eosinophilia are characterized by sustained eosinophilia and eosinophil-mediated tissue damage. Although treatment with the humanized monoclonal anti-IL-5 antibody SCH55700 resulted in improvement of eosinophilia and clinical symptoms in 6 of 8 of patients with hypereosinophilic syndrome or eosinophilic gastroenteritis with peripheral eosinophilia for as long as 12 weeks, eosinophil counts subsequently rose above baseline levels, accompanied by an exacerbation of symptoms. OBJECTIVE: To identify the mechanism underlying this rebound eosinophilia. METHODS: Purified eosinophils from patients or normal donors were cultured with IL-5, patient serum, and/or anticytokine antibodies, and eosinophil survival was assessed by flow cytometry. Serum and intracellular cytokine levels were measured by multiplex sandwich ELISA and flow cytometry, respectively. RESULTS: Before treatment with SCH55700, in vitro eosinophil survival in media and in response to recombinant IL-5 was similar in patients and normal donors. At 1 month posttreatment, the eosinophil survival curves were unchanged in 4 of 5 patients in media and in all 5 patients in response to recombinant IL-5. Normal eosinophil survival was prolonged in cultures containing posttreatment but not pretreatment sera (pretreatment vs posttreatment, 10.74% vs 73.02% live cells; P = .01). This posttreatment serum effect on eosinophil survival was reversed by the addition of the monoclonal anti-IL-5 antibody TRFK5. Although increased levels of serum IL-5 were observed at 1 month compared with 2 to 3 days posttreatment in 5 of 6 patients ( P = .04), intracellular cytokine analysis did not reveal increased production of IL-5 by peripheral blood mononuclear cells. CONCLUSIONS: The rebound eosinophilia after SCH55700 treatment is a result of a serum factor that enhances eosinophil survival. Reversal of this effect by the addition of antibody to IL-5 suggests that this factor may be IL-5 itself.

Adult↗
PubMed2005

Secretory IgA induces antigen-independent eosinophil survival and cytokine production without inducing effector functions.

BACKGROUND: Eosinophils in human beings reside in tissues, especially the mucosal tissues of the gastrointestinal tract and inflamed airways. Secretory IgA (S-IgA) is the predominant antibody secreted by these tissues and likely plays a role in the innate immune response. OBJECTIVE: Because eosinophils and S-IgA are often colocalized in mucosal tissues, we examined the potential regulatory effects of S-IgA without antigens on survival, gene expression, and effector functions of human eosinophils. METHODS: Eosinophils were incubated with S-IgA in solution without antigens (soluble S-IgA) or with S-IgA immobilized to mimic multivalent antigen cross-linking. Eosinophil activation was monitored by superoxide anion generation and degranulation. Survival was assessed between 24 and 96 hours. Gene and protein expression were examined by microarray and ELISA. Eosinophil lysates were examined by immunoblot for extracellular signal-regulated kinase (ERK) phosphorylation. RESULTS: Immobilized S-IgA stimulated eosinophil superoxide production and degranulation; soluble S-IgA did not. Although immobilized S-IgA inhibited eosinophil survival in vitro, soluble S-IgA enhanced survival; this involved autocrine production of GM-CSF. Soluble S-IgA without antigens induced increases in mRNA levels of various cytokines, chemokines, signal transduction molecules, antiapoptotic factors, and cell surface markers. By using ELISA, we confirmed protein expression of selected mediators. Eosinophil interaction with soluble S-IgA likely involves FcalphaRI (CD89) and ERK pathway activation. CONCLUSION: Secretory IgA without multivalent antigens may regulate survival and gene expression of eosinophils. Eosinophils in mucosal tissues can be either primed for action (cytokine production and survival) or fully activated (degranulation and superoxide release) by different forms of S-IgA.

Cell Degranulation↗
PubMed2006

Montelukast regulates eosinophil protease activity through a leukotriene-independent mechanism.

BACKGROUND: Migration of eosinophils into bronchial mucosa requires proteolysis. Montelukast, a cysteinyl leukotriene (CysLT) 1 receptor antagonist used in asthma treatment, decreases eosinophil infiltration into the asthmatic airways, suggesting that CysLTs modulate eosinophil protease activity. OBJECTIVE: We sought to determine whether CysLTs and montelukast regulate eosinophil protease activity. METHODS: Purified blood eosinophils were treated with or without montelukast; MK-0591, a 5-lipoxygenase-activating protein inhibitor; or leukotriene (LT) D(4). Migration assays through Matrigel were performed in the presence of 5-oxo-6,8,11,14-eicosatetraenoic acid (5-oxo-ETE), a potent eosinophil chemotactic factor, or LTD(4). Expression of molecules implicated in plasmin generation and matrix metalloproteinase (MMP) 9 release were also evaluated. RESULTS: Montelukast and MK-0591 decreased eosinophil migration promoted by 5-oxo-ETE, whereas LTD(4) failed to induce eosinophil migration. However, LTD(4) significantly boosted the migration rate obtained with a suboptimal concentration of 5-oxo-ETE and partially reversed the inhibition obtained with MK-0591. Montelukast significantly reduced the maximal rate of activation of plasminogen into plasmin by eosinophils obtained with 5-oxo-ETE. 5-Oxo-ETE increased the number of eosinophils expressing urokinase plasminogen activator receptor and stimulated secretion of MMP-9. Montelukast, but neither MK-0591 nor LTD(4), reduced the expression of urokinase plasminogen activator receptor and the secretion of MMP-9 and increased total cellular activity of urokinase plasminogen activator and the expression of plasminogen activator inhibitor 2 mRNA. CONCLUSION: Montelukast inhibits eosinophil protease activity in vitro through a mechanism that might be independent of its antagonist effect on CysLT 1 receptor. CLINICAL IMPLICATIONS: This could partially explain montelukast's anti-inflammatory effect in asthma and eventually amplify to improve its therapeutic efficacy.

Acetates↗