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Serum-soluble TRAIL levels in patients with severe persistent allergic asthma: its relation to omalizumab treatment.
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PMID:  22367138     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
BACKGROUND: In this study we compare the Omalizumab treatment modality in the dynamics of cell apoptosis regulating molecules in both severe persistent asthma patients who had no other any allergic disease, newly diagnosed patients with allergic asthma, and healthy volunteers.
MATERIAL/METHODS: Severe persistent allergic asthma patients were subjected to measurement of serum soluble TRAIL (TNF-related apoptosis-inducing ligand) levels during the active disease phase and the stable phase which occurred 4 months after Omalizumab treatment. Serum sTRAIL concentrations were measured by a solid phase sandwich enzyme-linked immunosorbent assay. Concentration levels were compared with those of age- and sex-matched newly diagnosed patients with allergic asthma, and healthy controls. All assays were carried out in duplicate. Total serum IgE levels, antinuclear antibody (ANA), rheumatoid factor (RF), hepatitis markers, C3, C4 and eosinophil levels were evaluated in all patients.
RESULTS: ANA, RF, hepatitis markers were negative in all patients. Complement 3 and 4 levels were normal in all patients. Prick tests in all patients were detected in mite and grass allergy. These results correlated with specific IgE. There were no differences between the healthy controls, newly diagnosed allergic asthma patients, and non-treated severe persistent allergic asthma patients during the active phase. Interestingly, the levels in variances of the patients who had the effective omalizumab treatment were significantly lower than the healthy controls, while the mean values were not statistically significant.
CONCLUSIONS: Our study gives a different perspective on severe persistent allergic asthma and omalizumab treatment efficacy at the cell apoptosis-linked step by the serum sTRAIL levels.
Authors:
Arzu Didem Yalcin; Atil Bisgin; Aysegul Kargi; Reginald M Gorczynski
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Medical science monitor : international medical journal of experimental and clinical research     Volume:  18     ISSN:  1643-3750     ISO Abbreviation:  Med. Sci. Monit.     Publication Date:  2012 Mar 
Date Detail:
Created Date:  2012-02-27     Completed Date:  2012-06-19     Revised Date:  2013-06-26    
Medline Journal Info:
Nlm Unique ID:  9609063     Medline TA:  Med Sci Monit     Country:  Poland    
Other Details:
Languages:  eng     Pagination:  PI11-5     Citation Subset:  IM    
Affiliation:
Allergy and Clinical Immunology Unit, Antalya Education and Training Hospital, Antalya, Turkey. adidyal@yahoo.com
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MeSH Terms
Descriptor/Qualifier:
Adolescent
Adult
Anti-Asthmatic Agents / therapeutic use*
Antibodies, Anti-Idiotypic / therapeutic use*
Antibodies, Antinuclear / blood
Antibodies, Monoclonal, Humanized / therapeutic use*
Asthma / blood*,  drug therapy,  etiology
Enzyme-Linked Immunosorbent Assay
Female
Humans
Hypersensitivity / blood*,  complications,  drug therapy
Immunoglobulin E / blood
Male
Middle Aged
Rheumatoid Factor / blood
TNF-Related Apoptosis-Inducing Ligand / blood*
Young Adult
Chemical
Reg. No./Substance:
0/Anti-Asthmatic Agents; 0/Antibodies, Anti-Idiotypic; 0/Antibodies, Antinuclear; 0/Antibodies, Monoclonal, Humanized; 0/TNF-Related Apoptosis-Inducing Ligand; 0/TNFSF10 protein, human; 0/omalizumab; 37341-29-0/Immunoglobulin E; 9009-79-4/Rheumatoid Factor
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Journal Information
Journal ID (nlm-ta): Med Sci Monit
Journal ID (iso-abbrev): Med. Sci. Monit
Journal ID (publisher-id): Medical Science Monitor
ISSN: 1234-1010
ISSN: 1643-3750
Publisher: International Scientific Literature, Inc.
Article Information
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© Med Sci Monit, 2012
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Received Day: 22 Month: 6 Year: 2011
Accepted Day: 20 Month: 9 Year: 2011
collection publication date: Year: 2012
Electronic publication date: Day: 01 Month: 3 Year: 2012
Volume: 18 Issue: 3
First Page: PI11 Last Page: PI15
PubMed Id: 22367138
ID: 3560751
Publisher Id: 882504

Serum-soluble TRAIL levels in patients with severe persistent allergic asthma: Its relation to omalizumab treatment
Arzu Didem Yalcin*1ABDEFG
Atil Bisgin*2CDE
Aysegul Kargi3CD
Reginald M. Gorczynski4ADEFG
1Allergy and Clinical Immunology Unit, Antalya Education and Training Hospital, Antalya, Turkey
2Department of Medical Genetics, Akdeniz University Faculty of Medicine, Antalya, Turkey
3Department of Medical Oncology, Denizli Education and Training Hospital, Denizli, Turkey
4Division of Cellular & Molecular Biology, Toronto Hospital, University Health Network, Toronto, ON, Canada
Correspondence: Arzu Didem Yalcin, Allergy and Immunology Unit, Antalya Education and Research Hospital, Antalya, Turkey, e-mail: adidyal@yahoo.com
*A.D.Y. and A.B. contributed equally to this article
AStudy Design
BData Collection
CStatistical Analysis
DData Interpretation
EManuscript Preparation
FLiterature Search
GFunds Collection

Background

Asthma is a chronic inflammatory disease that affects people of all ages, with the increasing total prevalence rate [1,2]. Asthma is a clinical diagnosis that incorporates genetic predisposition and clinical symptoms with objective measures of lung function and disease severity, and is determined by pulmonary function measurements, asthma symptoms, and the need for rescue medication [3,4]. While asthma is classified based on severity, at the moment there is no clear method for classifying different subgroups of asthma beyond this system, and in the most severe form, called ‘Severe persistent allergic asthma’, diagnosis is based on whether symptoms are precipitated by allergens [5,6]. Different patients will respond differently to the same treatment, thus it is clear that the cases within a classification have significant differences. Finding ways to identify patients who will respond well to different types of treatments is a current critical goal of asthma research.

Omalizumab (trade name Xolair), a recombinant humanized monoclonal antibody to IgE, is recommended as a new option for the treatment of severe persistent allergic (IgE mediated) asthma [7,8]. In our previous study, we reported the omalizumab treatment is clinically effective in severe persistent asthma patients with co-morbid allergic conditions [9].

Apoptosis (programmed cell death) is an active physiological process that leads to the ordered destruction of cells without the release of intracellular contents into the extracellular environment (which would cause an inflammatory reaction and tissue damage) [10]. Apoptosis in the immune system is a fundamental process regulating the maturation and homeostasis of the lymphocytes. It can be induced passively through the lack of essential survival signals, or actively, through the ligand induced trimerization of specific death receptors of the tumour necrosis factor (TNF) receptor family, such as Fas, the TNF receptor, or the TNF-related apoptosis-inducing ligand (TRAIL) receptor [11].

The Fas/FasL system plays a crucial role in apoptosis in many diseases, including cancer and inflammatory diseases [12]. The importance of the other death pathways is, however, uncertain. Recent interest has focused on TRAIL, with several studies indicating that sTRAIL is involved in the pathophysiology of different disease states, including cancer, viral infections, autoimmune diseases and inflammation. Defective apoptosis due to its interaction with its ligand preventing signaling for apoptosis may contribute to these diseases [1323].

Previously, it was reported that allergic rhinitis is a sFas-reduced disease, and it was suggested that sFas might play a new role in allergic rhinitis [24]. Previous studies also showed unexpected difference in serum sFas levels between allergic rhinitis patients and bronchial asthma patients, but no difference in sFas-L between the adults with asthma and healthy controls [24,25]. These studies suggested the possibility of different apoptosis systems in the pathogenesis of the allergic diseases.

TRAIL (APO-2 ligand) is a transmembrane (type II) glycoprotein which also belongs to the TNF superfamily. The extracellular domain of TRAIL is homologous to that of other family members and shows a homotrimeric subunit structure. Like TNF and FasL, TRAIL also exists physiologically in a biologically active soluble homotrimeric form [26].

In this study, our aim was to identify the role of sTRAIL in the pathophysiology of allergic asthma and in omalizumab efficacy as a new treatment modality in severe asthma in general.


Material and Methods
Patients

The study was approved by the local ethics committee, and written consent was obtained from all patients and healthy volunteers. In the first group, 14 patients (6 males and 8 females) with severe persistent asthma were selected whose mean age was 42.4 (±4.6) years and having asthma symptoms more than 5 years, were included in the study. All of these patients received omalizumab therapy for 4 months. Omalizumab was administered according to the product label every 2 weeks. The symptoms and severity of allergic reactions were recorded before and after the omalizumab therapy. Assessments of clinical changes and adverse effects were made at every bimonthly patient visit. For the clinical evaluation, the daytime symptom frequency and night-time symptom frequency was estimated, together with the lung function (PEF and FEV1 values) (data not shown).

In the second group there were 14 newly diagnosed allergic asthma patients who did not basically overlap with other allergic diseases. Mean age was 43.8 (±4.8) years. All patients were followed in the Immunology and Allergy Clinic of Antalya Education and Training Hospital, and were evaluated by clinical status (Table 1).

In the third group, there were 14 age- and sex-matched healthy individuals with 43.3 (±4.5) years mean age.

Blood collection

Total serum IgE levels, antinuclear antibody (ANA), rheumatoid factor (RF), hepatitis markers, C3, C4 and eosinophil levels were evaluated in all patients.

Total and specific IgE levels were estimated by fluoroenzyme immunoassay (ImmunoCAP-FEIA) using an ImmunoCAP (Pharmacia, Uppsala, Sweden) kit. Values above 100 kU/L and 0.35 kU/L for total and specific IgE levels, respectively, were considered abnormal.

Serum sTRAIL levels were measured by a sandwich enzyme-linked immunosorbent assay (Diaclone, France) in all participants.

Skin-Prick Test (SPT)

Skin prick tests on the forearm were performed in all patients using standardized latex extract containing high ammonia natural rubber latex, and a full set of 35 common and 35 food allergens. In addition, honey bee venom SPT was performed on 1 patient based on the subject’s clinical history. SPTs were performed by skilled nursing personnel. Positive tests were counted as wheals of 3 mm in diameter after 20 minutes. Tests were compared with positive histamine controls and negative saline controls. Commercial extracts used were manufactured by Alyostal ST-IR (Starallergenes S.A.-France). No intradermal tests were performed.

Statistical analysis

The results of patients in both groups were compared with those of healthy subjects. These data were statistically analyzed by using SPSS version 13.0 for Windows (SPSS Inc., Chicago, IL, USA). Inter-group comparisons were made using the independent samples T test. Intra-group comparisons were evaluated with the Wilcoxon’s matched-pairs signed-rank test.


Results

In this clinical follow-up study, 14 patients had already been receiving omalizumab therapy and these subjects were included for further analysis. The patients had had severe persistent asthma for periods ranging from 2 to 5 years, and had been diagnosed as having allergic asthma for 5–25 years. The study subjects’ baseline characteristics are shown in Tables 1 and 2.

The mean total serum IgE levels were as follows: in Group I, 459.785 IU/mL; in Group II, 124.8 IU/mL; and in Group III, 39.88 IU/mL. ANA, RF and hepatitis markers were negative in all patients. Complement 3 and 4 levels were normal in all patients. Prick tests in both patient groups (Group I and II) were positive for mite, and grass allergens. These results correlated with specific IgE.

As shown in Figure 1, there were no differences in the mean values of sTRAIL levels between the severe persistent allergic asthma patients before the omalizumab treatment (n=14; mean ±SD 1663±120.4 pg/ml), newly diagnosed allergic asthma patients (n=14; mean ±SD 1873±142.9 pg/ml), and healthy controls (n=14; mean ±SD 1751±161.6 pg/ml). But in contrast, serum sTRAIL levels in patients with severe persistent allergic asthma after the omalizumab treatment (n=14; mean ±SD 1443±80.93 pg/ml) were lower than those in healthy individuals (n=14; mean ±SD 1751±161.6 pg/ml).

However, 3 of 14 severe persistent allergic asthma patients showed an increase or no change in sTRAIL levels (Figure 2). Those patients (n=3) whose sTRAIL levels were increased or not changed, are the patients in whom the omalizumab treatment was clinically effective after the twelfth dose, while the other patients had a decrease in symptoms, mostly after the second or third dose. The patient whose sTRAIL level was increased about 2-fold was the patient who had newly diagnosed diabetes mellitus after the omalizumab treatment had started. However, the circulating soluble TRAIL is a negative marker for inflammation, and the levels were affected by autoimmune conditions [14,17].


Discussion

As a mechanism in allergic conditions, there was an increase in both T and B cells and eosinophils in both of our 2 patient groups. IT was previously reported that the increase in the eosinophil levels in allergic asthma was due to the increase in peripheral blood eosinophil survival promoted by TRAIL [13]. The exact role of TRAIL in vivo still remains unknown. In this study, we showed that soluble TRAIL levels of severe persistent allergic asthma patients were decreased after the anti-IgE treatment using omalizumab. The TRAIL levels of only 1 patient increased after omalizumab treatment. The possible explanation of the 2-fold increase in this patient may be due to the uncontrolled, newly-diagnosed diabetes mellitus (glucose levels were higher than 400 mg/dl and the patient was not using any anti-diabetic drugs).

These results suggest that TRAIL may act as a soluble effector, and the decrease after the omalizumab treatment may be an indicator of clinical improvement.

Omalizumab was evaluated as a treatment for asthma in large, multicenter, double-blind placebo control trials involving patients with moderate to severe asthma who required corticosteroids; when added to oral or inhaled corticosteroids, omalizumab reduced symptoms and exacerbations, improved lung functions and quality of life [27].


Conclusions

The physiological functions of sTRAIL in allergic conditions, and the elucidation of the molecular mechanisms of the TRAIL signaling pathways, will be of significant interest to the scientific allergy community in the coming years.


Notes

fn9-medscimonit-18-3-pi11Competing interests

The authors declare that they have no competing interests.

fn10-medscimonit-18-3-pi11Authors’ contributions

ADY was involved in patient recruitment, followed-up the patients, participated in the design of the study and drafted the manuscript. AB carried out the immunoassays, participated in its design and drafted the manuscript. AK researched the literature and participated in coordination. RMG drafted the manuscript and participated in its coordination. All authors read and approved the final manuscript.

fn11-medscimonit-18-3-pi11Source of support: Departmental sources

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Article Categories:
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Keywords: severe persistent allergic asthma, allergic asthma, soluble TRAIL, omalizumab.

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