Increase In Eotaxin Research Articles

The interplay between systemic inflammatory factors and endometriosis: A bidirectional mendelian randomization study

ObjectiveTo utilize vast genetic data to reveal the interplay between 41 systemic inflammatory factors and endometriosis. DesignBidirectional Mendelian randomization study. Mains outcome measuresThis study obtained believable genetic instrumental variables for systemic inflammatory factors. The effect of systemic inflammatory factors on different endometriosis phenotypes, and the effect of endometriosis on the concentrations of systemic inflammatory factors were investigated. ResultsIn this mendelian randomization study, we found 20 causal relationships involving 18 systemic inflammatory factors and it was shown that Monocyte chemotactic protein-1, Macrophage inflammatory protein-1a, Granulocyte colony-stimulating factor, Macrophage migration inhibitory factor, Interleukin-4, Interleukin-5, Interleukin-8, Interleukin-9, Interleukin-12p70, Interleukin-16, and Interleukin-17 may be the upstream causes of endometriosis (P<0.05). Additionally, if the definition of exposure in the mendelian randomization was endometriosis, it could suggestively cause an increase in Eotaxin, cutaneous T-cell attracting chemokine, and Interferon gamma-induced protein 10 levels, and a decrease in growth-regulated oncogene-alpha, Interleukin-2 receptor, alpha subunit, platelet-derived growth factor BB, and Interleukin-18 (P<0.05). Reverse causality was not observed between a single systemic inflammatory factor and endometriosis. ConclusionsOur findings indicate that several systemic inflammatory factors may act as the initiator at the onset of endometriosis. Additionally, several other inflammatory factors are far more probable to involved downstream during disease development.

Phase 2 Trial of Single-Agent Cobimetinib for Adults with BRAF V600-Mutant and Wild-Type Histiocytic Disorders

Background: Use of BRAF inhibitors in BRAFV600 mutant Erdheim-Chester disease (ECD) and Langerhans cell histiocytosis (LCH) leads to near universal and prolonged response and has transformed the management of these disorders. However, nearly 50% of histiocytosis patients lack a BRAFV600-mutation and therefore cannot receive BRAF inhibitors creating an ongoing need for new therapies in histiocytosis. Comprehensive profiling of these BRAFV600 wildtype (BRAF-wt) ECD/LCH patients has demonstrated that nearly all harbor mutations activating the Mitogen Activated Protein Kinase (MAPK) pathway. This finding raised the possibility of treatment of BRAF-wt histiocytosis with MEK1/2 inhibition. Here we present data on 11 patients with histiocytosis treated with single-agent of the MEK1/2 inhibitor Cobimetinib (Clinicaltrials.gov, NCT02649972).Methods: This is an open-label phase 2 trial of Cobimetinib 60mg daily for patients with (1) BRAF-wt histiocytosis or (2) BRAFV600-mutant histiocytosis intolerant or without access to BRAF inhibitor therapy. The primary outcome is metabolic response by 18F-FDG PET scan. Maximal FDG standardized uptake value (SUV) was observed in up to 5 target lesions, normalized for body weight; this was compared between baseline and subsequent scans. Secondary endpoints included progression-free survival (PFS) as determined by 18F-FDG PET scan, overall survival (OS), and patient-centered outcomes measuring disease-related symptoms (with a disease-specific symptom scale), symptoms of systemic inflammation (Sickness Behavior Inventory; SBI), and psychological states (Hospital Anxiety and Depression Scale). Based on prior data identifying systemic immune perturbation in the sera of histiocytosis patients, we quantitatively analyzed 40 cytokines, chemokines, and growth factors in serial sera of the patients in this trial. Data cut-off was June 22, 2017.Results: 11 patients (8 ECD, 1 Rosai-Dorfman disease [RDD], 1 mixed ECD/RDD, 1 LCH) have enrolled with a median age of 53. Eight patients have BRAF-wt disease, the remainder are BRAFV600-mutant positive. Ten patients have had response assessments at the time of data cut-off. The response rate was 90% (9/10), with 40% (4 patients) having a complete metabolic response (resolution of FDG avidity to organ background), 50% (5 patients) a partial metabolic response (50% or greater reduction in FDG avidity), and 10% (one patient) stable metabolic disease (Figure A-B). No patient has developed progressive disease. Mean symptom severity (scored 0-50) decreased by 31% (mean score 38 to 27) after 4 cycles of treatment for 9 patients with longitudinal assessment. 8 of these 9 patients with either anxiety or depression at baseline, and 4 had neither after 4 cycles of treatment. Mean SBI (scored 0-36) decreased 39% (mean score 22 to 13) in 5 patients with longitudinal assessment (Figure C). Cytokine analysis identified dramatic effects of Cobimetinib upon reducing IL-8, TNF-alpha, and MIP1b levels (amongst other cytokines) as well as coordinate increase in eotaxin and Flt3-L levels (Figure D). One patient died on study from Grade 5 respiratory failure, unrelated to drug, and one patient was removed from study due to drug toxicity (Grade 3 retinal vein occlusion). Grade 3/4 toxicities have been decreased lymphocyte count (23%), hyponatremia (23%), increased lipase (15%), diarrhea (8%), and hypocalcemia (8%).Conclusions: This trial demonstrates robust efficacy of single-agent MEK1/2 inhibition with Cobimetinib in histiocytic disorders, across both BRAF-wt and BRAFV600-mutant patients, measured by radiologic as well as patient-centered outcomes. Toxicities have been manageable and largely similar to those observed in previous trials of Cobimetinib. These data extend the spectrum of patients eligible to be treated with therapies targeting the activating somatic MAPK alterations driving histiocytoses. [Display omitted] DisclosuresDogan:Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche Pharmaceuticals: Consultancy; Peer Review Institute: Consultancy; Seattle Genetics: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy.

Ginsenoside Rh1 attenuates ovalbumin-induced asthma by regulating Th1/Th2 cytokines balance.

Ginsenoside Rh1 (Rh1) has anti-inflammatory effects in asthma mice, but the underlying mechanism remains unclear. BALB/c mice were sensitized and challenged with ovalbumin (OVA) to construct asthma model. Mice received Rh1 or tiotropium bromide 0.5 h before OVA challenge. Airway morphology and airway remodeling were assessed by HE staining and Masson's trichrome staining, respectively. Th1/Th2 cytokines in serum or broncho alveolar lavage fluid (BALF) were measured by ELISA kits. Rh1 significantly alleviated the lung resistance and airway resistance, and reduced the number of total inflammation cells, eosinophils, neutrophils, and lymphocytes in BALF of the asthmatic mice. The morphological changes and collagen deposition of airway were also reduced by Rh1 in asthmatic mice. The increase of Eotaxin, IL-4, IL-5, IL-13, and IL-33 and the decrease of IL-12 and IFN-γ in both BALF and serum of OVA exposed mice were reversed by Rh1. Rh1 attenuates OVA-induced asthma in the mice model by regulating Th1/Th2 cytokines balance.

Identifying Cytokine Biomarkers of Response to Pegylated-Interferon Therapy in Polycythemia Vera and Essential Thrombocythemia: Correlative Analysis from the MPN-RC 111/112 Trials

Background: Pegylated Interferon-alpha (PEG-IFNa) improves hematologic parameters and reduces mutant allele fraction in patients with myeloproliferative neoplasms (MPNs); however, widespread clinical use is limited by frequent discontinuation due to side effects. Identifying biomarkers of response to PEG-IFNa therapy might identify patient subsets most likely to derive benefit from this therapy. Serum pro-inflammatory cytokine levels are increased in MPN patients and associated with adverse clinical outcomes. The effect of PEG-IFNa therapy on cytokine levels in MPN patients and correlation with clinical response has not been elucidated. We hypothesized that identification of cytokine signatures could predict for clinical/molecular response to PEG-IFNa in MPNs. Methods: Pre- and post-treatment serum samples were collected from available patients enrolled on the Myeloproliferative Disorders Research Consortium (MPD-RC) 111/112 trials-multicenter studies assessing efficacy of PEG-IFNa in patients with high-risk polycythemia vera/essential thrombocythemia either up front or in the setting of hydroxyurea failure/intolerance. Serum was prepared using the Millipore MAP Human 41-Cytokine Magnet Bead System (Millipore; Cat:HCYTOMAG-60K) and run on the Luminex FLEXMAP 3D platform. Data was analyzed using Luminex xPonent 4.3 software. Correlative mutational data on 156 genes implicated in myeloid malignancies was also available for all patients. Age-matched serum from healthy individuals (N=6) was obtained from AllCellsTM for use as wild-type (WT) controls. Baseline cytokine samples were compared between groups of interest by use of Wilcoxon rank-sum test. Change from baseline in cytokines for each group were compared to the null hypothesis of zero change. P values &lt;0.05 were considered statistically significant. Results: Pre- and post-treatment serum samples were available on 29 MPN patients from the MPN-RC 111/112 cohorts. 21 patients were classified as complete responders (CRs) vs. 8 non-responders (NRs) using European LeukemiaNet criteria. Baseline cytokine levels were generally increased in both CRs and NRs compared to WT, including significant increases in Eotaxin (p=0.023), IL3 (p=0.048), IP10 (p=0.04), and TNFa (p=0.006) (Table 1), as well as a non-significant trend increase in IL8 (p=0.076). Notably, other cytokines were decreased at baseline in comparison to WT, including EGF (p&lt;0.001), as well as MDC (p=0.040) and PDGFaabb (p=0.02), in line with previous studies. Compared to CRs, NRs displayed significantly lower levels of GRO (p=0.020), MDC (p=0.003), and PDGFaabb (p=0.026) at baseline along with elevated levels of IP10 (p=0.028) suggesting pre-treatment levels of these cytokines might predict response to therapy. Comparison of pre- and post- treatment samples revealed a general increase in median cytokine levels in CRs, with significant changes in GM-CSF (p=0.012), IP10 (p&lt;0.001), MCP1 (p=0.015) and IFNa itself (p=0.010). Notably, median cytokine levels in NRs post-treatment, including IFNa, were relatively unchanged from baseline despite on-going PEG-IFNa therapy. Additional pre-treatment serum samples, as well as correlative analysis of cytokine changes with JAK-STAT driver mutant allele fraction and mutational profiling are underway and will be presented at the meeting. Conclusions: Preliminary findings suggest individual cytokines are affected by PEG-IFNa in MPNs. Furthermore, baseline levels of GRO, MDC, PDGFaabb, and IP10 correlate with response to PEG-IFNa. These data may identify MPN patients most likely to respond to PEG-IFNa therapy and those for whom this therapy may be most appropriate. Further analysis with a larger cohort of treatment-naïve patients is underway to validate these findings and identify additional molecular and cytokine signatures of response to PEG-IFNa therapy. Disclosures Yacoub: Agios: Speakers Bureau; Hylapharm: Equity Ownership; Dynavax: Equity Ownership; Cara: Equity Ownership; Ardelyx: Equity Ownership; Incyte: Consultancy, Honoraria, Speakers Bureau; Seattle Genetics: Honoraria, Speakers Bureau; Novartis: Consultancy, Speakers Bureau. Mascarenhas:Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Research Funding; Roche: Consultancy, Research Funding; Merck: Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; CTI Biopharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Research Funding; Promedior: Research Funding; Merus: Research Funding; Pharmaessentia: Consultancy, Membership on an entity's Board of Directors or advisory committees. Levine:Lilly: Honoraria; Qiagen: Membership on an entity's Board of Directors or advisory committees; Imago Biosciences: Membership on an entity's Board of Directors or advisory committees; Loxo: Membership on an entity's Board of Directors or advisory committees; Prelude Therapeutics: Research Funding; Isoplexis: Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Research Funding; Gilead: Consultancy; Amgen: Honoraria; C4 Therapeutics: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Research Funding; Novartis: Consultancy. Hoffman:Merus: Research Funding. Rampal:Constellation, Incyte, and Stemline Therapeutics: Research Funding; Agios, Apexx, Blueprint Medicines, Celgene, Constellation, and Jazz: Consultancy.

Neuroinvasion of Toxocara canis- and T. cati-larvae mediates dynamic changes in brain cytokine and chemokine profile

BackgroundNeurotoxocarosis (NT) is induced by larvae of the dog or cat roundworm (Toxocara canis or T. cati) migrating and persisting in the central nervous system of paratenic hosts, including humans, and may be accompanied by severe neurological symptoms. Host- or parasite-induced immunoregulatory processes contribute to the pathogenesis, but detailed data on pathogenic mechanisms and involvement of signalling molecules during cerebral Toxocara species infections are scarce.MethodsTo elucidate alterations in immunomodulatory mediator pattern, comprehensive multiplex bead array assays profiling comprising 23 different cytokines and chemokines were performed during the course of T. canis- and T. cati-induced NT. To this end, cerebra and cerebella of experimentally infected C57Bl/6 J mice serving as paratenic host models were analysed at six different time points (days 7, 14, 28, 42, 70 and 98) post infectionem (pi).ResultsBrain-body mass ratios of T. canis and T. cati-infected mice were significantly lower than those of the uninfected control group at day 14 pi, and also at day 28 pi for T. canis-infected mice. Both infection groups showed a continuous decrease of pro-inflammatory cytokine concentrations, including TNF-α, IFN-γ, GM-CSF and IL-6, in the cerebrum over the course of infection. Additionally, T. canis but not T. cati-induced neurotoxocarosis was characterised by significantly elevated levels of anti-inflammatory IL-4 and IL-5 in the cerebrum in the acute and subacute phase of the disease. The higher neuroaffinity of T. canis led to a prominent increase of eotaxin and MIP-1α in both the cerebrum and cerebellum, while in T. cati-infected mice, these chemokines were significantly elevated only in the cerebellum.ConclusionsThe direct comparison of T. canis- and T. cati-induced NT provides valuable insights into key regulatory mechanisms of Toxocara species in paratenic hosts. The cerebral cyto-/chemokine milieu is shifted to a predominantly anti-inflammatory immune response during NT, possibly enabling both survival of the parasite and the neuroinfected paratenic host. Alteration of eotaxin and MIP-1α concentrations are congruent with the higher neuroaffinity of T. canis and species-specific tropism of T. canis to the cerebrum and T. cati to the cerebellum.

Regorafenib Prior to Selective Internal Radiation Therapy Using 90Y-Resin Microspheres for Refractory Metastatic Colorectal Cancer Liver Metastases: Analysis of Safety, Dosimetry, and Molecular Markers.

Background: This Phase II, open-label, study examined the safety of regorafenib followed by selective internal radiation therapy (SIRT) with regorafenib re-initiation in the treatment of metastatic colorectal cancer (mCRC) patients with liver metastases who are not surgical candidates.Methods: Patients received 160 mg regorafenib daily on a 21-day course followed by a 1 week washout prior to SIRT. Liver function was evaluated at 2 and 4 weeks after SIRT, and regorafenib re-initiated if liver function was normal. Patients were evaluated for safety, and restaged at weeks 6 and 12 following SIRT. In addition, protein and cytokine assays of blood were performed to identify candidate molecular biomarkers associated with outcomes. Individual patient voxel-based dosimetry assessment was performed post-SIRT.Results: Twenty-Five patients were enrolled and received a median 11 weeks regorafenib. Three patients received regorafenib, but not SIRT due to disease progression. The remaining 22 patients received SIRT with a median activity delivered to the liver of 38 mCi, mean normal liver dose of 14.98 Gy and tumor mean dose of 29.0 Gy with a tumor to normal ratio mean of 2.42. There were four treatment-related serious AEs and no treatment-related deaths. Median progression-free survival was 3.7 months and the median overall survival was 12.1 months. The relative densities of several biomolecules changed significantly during the course of treatment, most notably post-treatment increases in levels of sex-hormone binding globulin (SHBG) and decreased levels of the cytokine MIG (CXL9). Decreases in von Willebrand factor (VWF), the ankyrin repeat domain (ANKRD26), and MIG were associated with improved survival times. Post-treatment increases in alpha-2-macroglobulin (A2M) and the cytokine intercellular adhesion molecule (ICAM-1) were associated with reduced overall survival time, while increases in Eotaxin (CCL14) predicted longer overall survival times.Conclusions: The treatment of mCRC patients with liver metastases using regorafenib followed by SIRT was tolerable in this patient population. Further efficacy analysis of this treatment schema and analysis of potential molecular biomarkers using larger sample sizes is merited.

Quantitative analysis of serum chemokines associated with treatment failure of direct-acting antivirals in chronic hepatitis C

Although serum chemokine levels have been reported to influence the outcome of interferon-based treatment in patients with chronic hepatitis C, their effect on the hepatitis C virus (HCV) response to direct-acting antiviral agents (DAAs), which can achieve high rates of a sustained virological response (SVR), is largely unknown. To clarify this relationship, 9 chemokines (eotaxin, GRO-α, IL-8, IP-10, MCP-1, MIP-1α, MIP-1β, RANTES, and SDF-1α) were quantified before, during, and after DAA treatment using serum samples obtained from 57 patients with chronic hepatitis C. All baseline median chemokine levels were significantly higher in patients with chronic hepatitis C than in healthy subjects (P < 0.05). In particular, lower MIP-1β (≤71.5 pg/mL) and higher RANTES (>671.5 pg/mL) levels were significantly associated with patients who failed to clear HCV RNA (P = 0.0039 and 0.013, respectively). Prediction of a clinical response based on a combination of these chemokines demonstrated high sensitivity (82%), specificity (85%), negative predictive value (95%), and area under the curve (0.833). The non-SVR rate (56.3%; 9 of 16) was significantly higher in patients with low MIP-1β and high RANTES compared with other combinations. Moreover, baseline MIP-1β and RANTES were both additive and independent for predicting a non-SVR. Apart from an increase in eotaxin, all chemokines became decreased in patients with a SVR. In conclusion, a combination of serum MIP-1β and RANTES levels may be predictive of a treatment response to DAAs in Japanese patients with chronic hepatitis C.

Abstract 3191: Elevation of tumor-promoting cytokines in mice exposed to the environmental contaminant tributyltin

Abstract Cytokines are important regulators of immune responsiveness. Alterations of cytokine secretion from immune cells would have the potential to disrupt both immune destruction of cancer cells and to alter the proliferation and invasiveness of tumor cells due to their capacity to act as growth factors, angiogenic factors, and inducers of epithelial-mesenchymal transition. Tributyltin (TBT) is a widespread environmental contaminant having been used in a variety of industrial applications and is found in human blood at levels ranging as high as 261 nM. Studies in human immune cells have shown that secretion of tumor necrosis factor alpha (TNFα) is altered by exposures to TBT. There have been no in vivo studies of the effects of exposure to TBT on the cytokine communication network. As it is not possible to examine alterations of this network in exposed humans, we examined the effects of TBT exposure in a mouse model using Milliplex mouse cytokine/chemokine magnetic bead premixed 32 plex kit. Serum and spleens of TBT-exposed mice were analyzed for changes in cytokine secretion/levels. TBT increased the levels of IL13 in the serum of non-tumor-bearing mice and increased IL1β, IL6, KC, and M-CSF in tumor-bearing mice. The spleens of both non-tumor-bearing and tumor-bearing mice showed increases in Eotaxin when exposed to TBT. Of significant interest is the fact that the presence of tumor causes increases in Eotaxin, IL12p40, M-CSF, and TNFα and exposure to TBT alone can cause increases in these same cytokines. Tumors are known to increase levels of cytokines that enhance their ability to survive. The results showing that TBT can amplify the levels of several cytokines that are increased by tumor suggest that TBT may have tumor-promoting abilities by modulating tumor growth and/or invasiveness. Experiments are under way to dissect cytokine signaling pathways that are affected by TBT. The findings will allow identification of molecular targets that are necessary to intercept the tumor promoting signaling following TBT exposure. Supported by: NIH grant 5U54CA163066-03 Citation Format: Shanieek Lawrence, Samuel Troy Pellom, Tasia Hurd-Brown, Anil Shanker, Margaret Whalen. Elevation of tumor-promoting cytokines in mice exposed to the environmental contaminant tributyltin. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3191. doi:10.1158/1538-7445.AM2014-3191

MOLECULAR MECHANISMS OF FORMATION OF BLOOD EOSINOPHILIA UNDER PULMONARY TUBERCULOSIS

Molecular factors of pathogenesis of the eosinophilic blood reaction under pulmonary tuberculosis are analyzed in the article. It has been established that the key cytokine providing the development of hemic eosinophilia in patients with pulmonary tuberculosis is IL-5. IL-5 plasma concentration turned out to be increased only in patients with eosinophilia. Increase of eotaxin was determined in patients with tuberculosis despite of the presense of eosinophilia. One-directional nature of the defined changes in eotaxin concentration might be explained by dual properties of this chemokine: on the one hand, eotaxin mediates long-term presence of eosinophils in blood; on the other hand, it initiates the process of adhesion of eosinophilic leucocytes to vascular endothelium with their further migration to the focus of granulomatous inflammation. The established increase in number of IL-5R-positive eosinophils presents one more mechanism which explains the basis of long-term presence of eosinophils in peripheral blood in patients with pulmonary tuberculosis.

Eotaxin in Exhaled Breath Condensate of Allergic Asthma Patients with Exercise-Induced Bronchoconstriction

Background: Eosinophils are the key inflammatory cells in asthma, and more and more evidence suggests their crucial role in exercise-induced bronchoconstriction (EIB). Eotaxin, as the most important chemotactic factor for eosinophils, plays an important role in the pathogenesis of asthma. Objectives: The aim of the study was to evaluate the changes in eotaxin levels in exhaled breath condensate (EBC) following intensive exercise in allergic asthmatics. Methods: The study was performed in a group of 27 asthmatics (17 with EIB, 13 without EIB) and 9 healthy volunteers. Changes induced by intensive exercise in the concentrations of eotaxin in EBC during the 24 h after an exercise test were assessed. The possible correlations of these measurements with the results of other tests commonly associated with eosinophilic airway inflammation were also determined. Results: In asthmatic patients with EIB, a statistically significant increase in eotaxin concentrations in EBC collected during the first 24 h after an exercise test – with maximal increase after 6 h – was revealed. A statistically significant correlation between the maximum increase in eotaxin concentrations in EBC after exercise, and an increase in either serum eosinophil cationic protein or F_ENO 24 h after exercise in the group of asthmatics with EIB, was observed. Conclusions: Our results confirm connections between EIB and airway eosinophilic inflammation. The increase of eotaxin in asthmatic airways, by promoting the migration and activation of eosinophils, may play an important role in upregulation and sustaining of the airway inflammation observed in EIB in asthmatic patients.

Staphylococcus Aureus Increases Cytokine and Matrix Metalloproteinase Expression in Nasal Mucosae of Patients with Chronic Rhinosinusitis and Nasal Polyps

Staphylococcus aureus is a common bacterial pathogen associated with chronic rhinosinusitis with/without nasal polyps (CRSw/sNP). We investigated the effect of S. aureus on the secretion of eotaxin, interleukin (IL)-5, IL-8, IL-13, matrix metalloproteinase (MMP) 2, MMP-9, and tissue inhibitor of MMP (TIMP) 1 in nasal mucosae from CRSwNP patients to assess the roles of these materials in NP pathogenesis. We infected organ cultures of NP and inferior turbinate (IT) mucosae taken from patients with CRSwNP with S. aureus ATCC 25923 for 24 hours and incubated the cultures for an additional 48 hours at 37°C. S. aureus infection and staphylococcal enterotoxins were confirmed by real-time polymerase chain reaction. Eotaxin, IL-5, IL-8, IL-13, MMP-2, MMP-9, and TIMP-1 protein levels were measured by ELISA. S. aureus infection significantly increased the concentrations of eotaxin, IL-5, IL-8, and IL-13 in the IT and NP groups (p < 0.01 for all comparisons). S. aureus infection also significantly increased the concentrations of MMP-2, MMP-9, and TIMP-1 in both groups (p < 0.001 for all comparisons). After S. aureus infection, the relative increases in eotaxin (6.42 versus 3.56), IL-5 (15.29 versus 8.89), MMP-2 (1.95 versus 1.58), MMP-9 (2.34 versus 1.95), and TIMP-1 (1.45 versus 1.31) were greater in the NP group than in the IT group. S. aureus infection enhances the secretion of cytokines, MMP-2, MMP-9, and TIMP-1 by both NPs and IT mucosae from patients with CRSwNP. S. aureus may play an important role in the pathogenesis of NP via tissue remodeling as well as eosinophilic inflammation.

Natural killer cells suppress autoimmune myocarditis in mice (48.23)

Abstract Autoimmune myocarditis is induced by the adoptive immune response; however, there is evidence that the innate immune system plays a major role in modulating disease. Natural killer (NK) cells can function in early innate responses, as well affecting the later adaptive immune response. Depletion of NK cells has been shown to exacerbate the development of virus-induced myocarditis. We hypothesized that NK cells also modulate the virus-free model of myosin-induced experimental autoimmune myocarditis (EAM). To study the action of NK cells, we immunized BALB/c mice on days 0 and 7 with myocarditogenic peptide MyHC (614-629) in complete Freund adjuvant. The mice were treated with PBS, rabbit IgG or anti-asialo GM1 antibody every day for 6 days prior to the first immunization and every 2 days following day 0 until day 21. We found that depleting NK cells significantly increased the severity of disease, and serum antibodies specific to the myocarditogenic peptide. Splenic CD4+ T cells were significantly more activated in NK depleted mice compared to controls. Cytokine analysis of heart homogenates revealed a significant increase in eotaxin and IL-5 in the hearts of mice that were depleted of NK cells. Our data suggest that NK cells suppress the adoptive immune response and modulate eosinophil migration and T cell activation during EAM in mice.

Elevation of Plasma Eotaxin Levels in Children with Food Allergy

Eosinophils play an important role in allergic responses. Eotaxin is a CC chemokine that promotes the selective recruitment of eosinophils. This study was performed to investigate the significance of eotaxin in pediatric food allergies. The study population included 35 patients with food allergy, 18 patients with atopic dermatitis but without food allergy, and 19 age-matched non-allergic controls. Eotaxin-1 and eotaxin-3 levels in plasma were assayed by enzyme-linked immunosorbent assay. Simultaneously, eosinophil counts in peripheral blood and serum immunoglobulin E (IgE) values were assessed. Plasma eotaxin-1 levels were 93.6+/-33.4 pg/ml in patients with food allergy, 78.0+/-31.8 pg/ml in patients with atopic dermatitis, and 60.4+/-15.7 pg/ml in controls. Differences between the food allergy and control groups were significant (P<0.001). Circulating eosinophil counts in patients with food allergy were higher than those in controls (5.84+/-9.46x10(9)/l vs. 1.20+/-1.11x10(9)/l, P<0.001). Nevertheless, eotaxin-1 levels in children with food allergy were not correlated with eosinophil counts or serum IgE levels. There were no significant differences in eotaxin-3 levels between the 3 groups. Plasma levels of eotaxin-1 were elevated in children with food allergy. The pathophysiological relevance of the increase in eotaxin is discussed.

Systemic responses after bronchial aspirin challenge in sensitive patients with asthma

In aspirin-sensitive patients with asthma, bronchial obstruction induced by oral aspirin may be associated with extrabronchial symptoms, suggesting the systemic character of the response. Go assess potential systemic effects of local aspirin challenge, hemopoietic progenitors were measured in the peripheral blood of challenged patients. In 19 patients with a history of aspirin-induced asthma, placebo-controlled bronchial challenges with lysine-aspirin were performed. Peripheral blood was collected before and then 1 hour and 20 hours after challenge (placebo or aspirin). Using the flow-cytometric method, the numbers of leukocyte (CD34+ cells) and eosinophil (CD34+CD125+ cells) progenitors were determined. The challenge was positive in 13 patients; 6 patients had isolated local bronchial reaction, and 7 patients developed systemic symptoms (bronchial and extrabronchial). In patients with positive challenge (n = 13), leukocyte progenitors increased significantly at 1 hour and 20 hours after challenge (mean, 0.04% at baseline, 0.066% at 1 hour after challenge, and 0.073% at 20 hours; P < .05). Eosinophil progenitors raised significantly from mean 0.017% before challenge to 0.04% (P < .05) at 20 hours after the challenge. At 20 hours after the challenge, the increase in leukocyte and eosinophil progenitors was observed only in patients with systemic reactions. Positive aspirin challenge was associated with a significant increase in eotaxin 2 serum concentration. This study demonstrated that bronchial challenge with aspirin may involve systemic reactions and is associated with mobilization of leukocyte and eosinophil progenitor cells from the bone marrow.

Kinetics of change in the eotaxin concentration in serum and cerebrospinal fluid of mice infected with Angiostrongylus cantonensis.

The kinetics of changes in the eotaxin concentration in the serum and cerebrospinal fluid (CSF) of BALB/c mice after infection with Angiostrongylus cantonensis and the correlation between the concentration of eotaxin and worm recovery were investigated. The mean concentration of eotaxin in serum of infected mice gradually increased from 46.3+/-6.5 pg/ml at week 0 to 104.9+/-44.8 pg/ml at week 3 after infection, while the mean eotaxin level in the CSF of infected mice rapidly increased from 18.7+/-2.1 pg/ml to 193.2+/-23.6 pg/ml 1 week after infection and then increased further to 507.8+/-167.9 pg/ml at week 3. The concentrations of eotaxin in the CSF of infected mice each week after infection were all significantly higher than those in serum ( P<0.0001). In parallel with the increase in eotaxin in the CSF, infected mice showed gradual increases in CSF eosinophilia and a reduction in intracranial worm recovery. The concentration of eotaxin in CSF was higher in infected mice with more worms in the brain, except when the number of worms in the brain was >30. In addition, when the worm counts in the brains of infected mice were <30, eotaxin concentrations in the CSF were positively correlated with worm counts in the brain ( P<0.001). Thus, the release of eotaxin in the CSF of mice infected with A. cantonensis observed in this study was time dependent and worm-load dependent, and in parallel with the increase in eotaxin in the CSF, and gradual decreases in worm counts in the brains of infected mice.

Steroid‐sensitive indices of airway inflammation in children with seasonal allergic rhinitis

Previous studies involving adults have demonstrated that airway glucocorticosteroids inhibit plasma exudation and eosinophil activity in allergic rhinitis. This study explores the possibility that plasma exudation, exudative responsiveness, and the occurrence of eosinophil activity-related proteins are glucocorticosteroid-sensitive nasal mucosal indices in allergic children. Using a placebo-controlled, parallel-group design effects of nasal budesonide (64 microg per nasal cavity b.i.d) were determined in children with seasonal allergic rhinitis. Nasal lavage fluid levels of eotaxin, eosinophil cationic protein (ECP), and alpha2-macroglobulin, indicating plasma exudation, were determined, the latter with and without challenge with topical histamine. Nasal lavage fluid levels of alpha2-macroglobulin and ECP increased significantly during the pollen season, and the acute plasma exudation response to histamine was significantly greater during than outside the season. There was a trend towards a seasonal increase in nasal lavage fluid levels of eotaxin. Budesonide significantly inhibited the seasonal increase in alpha2-macroglobulin as well as the exudative hyperresponsiveness to histamine. Any tendency of increases in mucosal output of eotaxin and ECP was abolished by the glucocorticosteroid treatment. We conclude that mucosal exudation of plasma, as a global sign of active inflammatory processes, is a glucocorticosteroid-sensitive facet of allergic rhinitis in children. Exudative hyperresponsiveness, potentially caused by several weeks of mucosal inflammation, emerges as a significant feature of allergic rhinitis in children, and its development is prevented by local treatment with a glucocorticosteroid drug. The seasonal increase in ECP and the trend for an increase in eotaxin were absent in the glucocorticosteroid-treated subjects.

Beyond our pages

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Modulation of eotaxin formation and eosinophil migration by selective inhibitors of phosphodiesterase type 4 isoenzyme.

1. This study was undertaken to investigate the possible contribution of the blockade of eotaxin generation to the anti-eosinophilotactic effect of phosphodiesterase (PDE) type 4 inhibitors. In some experiments, the putative synergistic interaction between PDE type 4 inhibitors and the beta2-agonist salbutamol was also assessed. 2. Sensitized guinea-pigs aerosolized with antigen (5% ovalbumin, OVA) responded with a significant increase in eotaxin and eosinophil levels in the bronchoalveolar lavage fluid (BALF) at 6 h. Eosinophil recruitment was inhibited by both PDE type 4 inhibitors rolipram (5 mg kg(-1), i.p.) and RP 73401 (5 mg kg(-1), i.p.) treatments. In contrast, only rolipram inhibited eotaxin production. 3. Sensitized rats intrapleurally challenged (i.pl.) with antigen (OVA, 12 microg cavity(-1)) showed a marked eosinophil infiltration at 24 h, preceded by eotaxin generation at 6 h. Intravenous administration of a rabbit anti-mouse eotaxin antibody (0.5 mg kg(-1)) significantly reduced allergen-evoked eosinophilia in this model. 4. Local pretreatment with rolipram (40 microg cavity(-1)) or RP 73401 (40 microg cavity(-1)) 1 h before challenge reduced eosinophil accumulation evaluated in the rat pleural effluent, but only the former was active against eotaxin generation. The inhibitors of PDE type 3 (SK&F 94836) and type 5 (zaprinast) failed to alter allergen-evoked eosinophil recruitment in rats. 5. Local injection of beta2-agonist salbutamol (20 microg cavity(-1)) inhibited both eosinophil accumulation and eotaxin production following pleurisy. The former was better inhibited when salbutamol and rolipram were administered in combination. 6. Treatment with rolipram and RP 73401 dose-dependently inhibited eosinophil adhesion and migration in vitro. These effects were clearly potentiated by salbutamol at concentrations that had no effect alone. 7. Our findings indicate that although rolipram and RP 73401 are equally effective in inhibiting allergen-induced eosinophil infiltration only the former prevents eotaxin formation, indicating that PDE 4 inhibitors impair eosinophil accumulation by mechanisms independent of eotaxin production blockade.

Eotaxin and prednisolone concentrations regulate the mobilisation of peripheral blood eosinophils preceding heart allograft rejection

There is a generic relationship between early changes in peripheral blood eosinophil counts (EOS)and the development of clinically significant rejection following solid organ transplantation. In a randomized, controlled trial of EOS monitoring in 80 heart transplant (HTx) recipients we have further shown that suppression of EOS can be used as a highly cost-effective guide to corticosteroid administration in the control of rejection within the first 6 post-operative weeks. We have now assessed the relative impact of immunosuppressive drugs, including the plasma prednisolone (PRL)concentration (HPLC assay), as well as plasma concentrations of two eosinophil chemotactic and activating peptides that act through the CC-chemokine receptor-3 (CCR3), eotaxin and RANTES (immunometric assay), on the diagnostic changes in EOS that precede treated HTx rejection (usually ISHLT Grade ≥ 3A). The first 46 consecutive HTx recipients recruited to our randomised trial, with a median follow-up of 90 days, were included in the study. Univariate regression analysis showed that cyclosporin dose, blood cyclosporin concentration, azathioprine dose and plasma RANTES concentration were not related to EOS. Factors related to changes in EOS included plasma PRL, endogenous cortisol and eotaxin concentrations. Multivariate linear regression analysis, accounting for within and between-patient correlations, revealed that the most important factors influencing EOS were PRL (-31% change in EOS per 50μg/L increase in PRL; 95% CI −21, -40%; P<0.001) and eotaxin (+22% change in EOS per 100μg/L increase in eotaxin; 95% CI +6, +41%; P=0.006) in a negative and positive manner, respectively. Changes in EOS that precede HTx rejection are controlled by a balance between eotaxin-induced mobilisation and corticosteroid-induced suppression. The use of new selective CCR3 antagonists may help to elucidate the pathophysiological significance of eosinophils in allograft rejection.

Differential roles of IL-18 in allergic airway disease: induction of eotaxin by resident cell populations exacerbates eosinophil accumulation.

Cytokine regulation during an allergic response can dictate the severity of the inflammation and resulting injury. In the present study, we have examined the systemic and local effects of IL-18, a Th1-associated cytokine, on a cockroach allergen-induced airway response. In initial studies, temporal increases in IL-18 levels were observed within the lungs. When IL-18 was neutralized systemically the allergen-associated eosinophil accumulation was significantly accelerated 5-fold by 8 h postchallenge, suggesting a regulatory role for IL-18. Recombinant IL-18 (200 ng) was instilled into the airway at the time of allergen challenge to examine whether a direct impact on local eosinophil accumulation could be induced. When IL-18 was instilled, a significant increase in peribronchial eosinophil accumulation was observed in allergic mice as well as in nonallergic mice. A possible mechanism was observed in a significant increase in eotaxin, but not other eosinophil chemotactic factors, in bronchoalveolar lavage fluid after IL-18 instillation. The role of eotaxin was confirmed using eotaxin -/- mice, which demonstrated significantly less eosinophil accumulation compared with littermate controls. IL-18 was subsequently shown to induce eotaxin production from bronchial epithelial cells and isolated macrophages in in vitro assays. The clinical relevance of these findings was determined in treated mice and demonstrated that neutralization of IL-18 exacerbated, whereas exogenous IL-18 had no effect on airway hyperreactivity. Altogether, these data demonstrate that IL-18 may have multiple functions during an immune response that differ depending upon the local or systemic effects.