Childhood atopic asthma: positive association with a polymorphism of IL-4 receptor alpha gene but not with that of IL-4 promoter or Fc epsilon receptor I beta gene

We examined the relative contributions of three representative candidate genes for atopy (Fc epsilon receptor I beta, IL-4, and IL-4 receptor alpha) to the development of atopic asthma. Four polymorphisms of the three candidate genes including Ile50Val and Gln551Arg of IL-4 receptor alpha, -590C/T of IL-4 promoter and Glu237Gly of Fc epsilon receptor I beta were studied in 100 patients with atopic asthma and 100 nonatopic controls in the northern Kyushu area in Japan. Among the four polymorphisms of the three candidate genes, the Ile50 allele of the IL-4 receptor alpha chain gene demonstrated an association with atopic asthma subjects (p = 0.044), especially in patients with onset at 2 years of age or earlier (p = 0.034) and in patients with moderate to severe atopic asthma (p = 0. 031). Gln551Arg of IL-4 receptor alpha, -590C/T of IL-4 promoter and Glu237Gly of Fc epsilon receptor I beta showed no association with atopic asthma. A slight linkage disequilibrium between Ile50Val and Gln551Arg polymorphisms of the IL-4 receptor alpha chain gene was observed in both patients and nonatopic controls. The identification of additional atopy genes in areas with a certain genetic background is essential for genetic diagnosis and to establish new therapeutic modalities for atopic asthma.     

Current Status of Gene Therapy for Rheumatoid Arthritis

Despite the high prevalence of the disease, at present little effective pharmacological treatment of rheumatoid arthritis is available. Novel approaches utilising biological agents have resulted in the development of new antiarthritic and antiinflammatory agents, such as tumour necrosis factor-alpha (TNFalpha)-specific antibodies and interleukin-1 receptor antagonist (IL-1ra). Local gene therapy not only allows the pharmaceutical use of these biologicals, but also allows for continuous drug supply, which is necessary for chronic diseases like rheumatoid arthritis. We discuss the basics of rheumatoid arthritis therapy, candidate genes and possible gene transfer methods. A current clinical gene therapy trial is focusing on the IL-1 system using IL-1ra as a transgene. The transfer system, clinical protocol and preliminary results are described. After treatment of 11 patients we feel that gene therapy will offer potential as a new avenue to treat rheumatoid arthritis.     

Interleukin-2 receptor blockers in renal transplantation

The last two decades have witnessed significant advances in the renal transplantation immunosuppressive protocols. The introduction of mycophenolate mofetil, tacrolimus, sirolimus and polyclonal antibodies has significantly improved graft survival. However, intensification of immunosuppression results in complications such as malignant diseases, opportunistic infections and metabolic disturbances with consequential increase in cardiovascular mortality. Advances in molecular engineering have made possible the development of monoclonal humanized or chimeric antibodies, which will not induce the host immune response with production of neutralizing antibodies or serum sickness. Antibodies directed against the alpha chain of human IL-2 receptor have recently been introduced into immunosuppressive protocols. Daclizumab is a humanized antibody, and basiliximab is a chimeric antibody, engineered by cloning segments of the murine immunoglobulin sequence into the human-immunoglobulin gene. It decreases immunogenicity while maintaining high specificity for IL-2R alpha chain. The efficacy and safety of both preparations have been reported in large randomized studies. Their use in induction resulted in a significant decrease in acute graft rejections after renal transplantation. The possibility of decreasing the dose or complete withdrawal of certain immunosuppressive agents with the use of IL-2R blockers seems promising for further improvement in the longterm graft survival. Longterm follow-up is necessary to determine their role in solid organ transplantation.     

Inhibition of interleukin-5 gene expression by dexamethasone.

The effect of glucocorticoids on interleukin-5 (IL-5) gene expression was assessed in human peripheral blood mononuclear cells. IL-5 expression was stimulated by phytohaemagglutinin (PHA), IL-2, phorbol myristate acetate (PMA) or Ionomycin. A semi-quantitative assay for IL-5 gene expression was developed, based on RNA extraction and the polymerase chain reaction. IL-5 expression in response to PHA was profoundly inhibited by 10(-6) M dexamethasone, and significant inhibition was detected at doses of dexamethasone as low as 10(-9) M. When dexamethasone was added to the cells at the same time as PHA, the inhibitory effect could be detected as early as 3 hr. Dexamethasone at 10(-6) M also profoundly inhibited the IL-5 response to PMA and to IL-2, but the IL-5 response to Ionomycin was not significantly affected. These results suggest that dexamethasone may be capable of interfering with a pathway involving protein kinase C. There is increasing evidence that IL-5 may play a pathogenic role in asthma and other manifestations of acute hypersensitivity. The present findings indicate that inhibition of IL-5 expression may be one of the mechanisms whereby glucocorticoids exert their beneficial effects in diseases such as asthma.     

Global burden of disease--a race against time

Low-income communities will within the next decades undergo rapid changes. The burden of non-communicable diseases (NCDs), such as diabetes, cardio-vascular disease and cancer, will comprise an increasing proportion of the total disease burden. The results of projections indicate that the already constrained health systems will face a double burden of disease, in which HIV/AIDS and other common infectious diseases will co-exist with the new NCDs. In order for preventive measures directed towards NCD to be cost-effective, these have to be implemented within the next 10-20 years.     

The establishment of humanized IL-4/IL-4RA mouse model by gene editing and efficacy evaluation

Asthma is a common respiratory immune disease in children and adults, and interleukin-4 (IL-4) is one of the key factors for the onset of asthma. Therefore, targeting human IL-4 and IL-4 receptor alpha (IL-4RA) has become one of the strategies for targeted therapy of cytokines. Herein, we established an animal model of asthmatic airway inflammation using double humanized IL-4/IL-4RA (hIL-4/hIL-4RA) mice, where human IL-4 and IL-4RA replaced their murine counterparts, respectively. We successfully identified the phenotype by Southern blotting, ELISA, and flow cytometry. The hIL-4/hIL-4RA mice induced by ovalbumin (OVA) exhibited several important features of asthma, such as inflammatory cell infiltration, IgE release, goblet cell hyperplasia, and Th2 cytokine secretion. Furthermore, treatment of these humanized mice with anti-human IL-4RA antibodies significantly inhibited level of these pathological indicators. Thus, hIL-4/hIL-4RA mice provide a validated preclinical mouse model to interrogate new therapeutic agents targeting this specific cytokine pathway in asthma.     

Lack of association of atopy/asthma and the interleukin-4 receptor α gene in Japanese

BACKGROUND: Susceptibility to the development of atopic diseases is known to involve genetic factors. Several investigators have reported the interleukin-4 (IL-4) receptor alpha gene to be involved in the development of atopy. Recent study has shown that the R allele of a polymorphism in the IL-4 receptor alpha chain gene (Q576R) to be associated with atopy. OBJECTIVE: The objective of this study was to evaluate the possible role of the IL-4 receptor alpha gene in modulating allergic response and asthma in the Japanese population. METHODS: We conducted linkage analysis using microsatellite markers flanking the IL-4 alpha receptor gene in 82 families ascertained through asthmatic children. The IL-4 receptor Q576R polymorphism was also genotyped by PCR-restriction fragment length polymorphism analysis. RESULTS: We did not find evidence for linkage of the asthma and atopy phenotypes with the markers D16S298 and D16S403 (P = 0.10 and P = 0.56, respectively, for the atopy phenotype and P = 0.17 and P = 0.60, respectively, for the asthma phenotype). The IL-4 receptor R576 allele was not preferentially transmitted to atopy- or asthma-affected children (chi2 = 1.67, P = 0.24 for atopy and chi2 = 0.91, P = 0.40 for asthma). In addition, the prevalence of the R576 allele among parents with and without atopy was similar, 20 of 81 (24.7%) parents with atopy and 22 of 77 (28.6%) parents without atopy. CONCLUSION: Our findings indicate that the IL-4 receptor alpha gene does not exert a substantial influence on the inheritance of atopy or asthma in this Japanese population.     

Reducing IgE levels as a strategy for the treatment of asthma

IgE secretion by B lymphocytes defines the allergic state and nearly all asthmatics have higher than normal IgE levels in serum following adjustment for age and sex. It is thought that allergic mechanisms may be responsible for the increasing prevalence of asthma. In particular, in utero changes may encourage T cells to differentiate into Th₂ subtypes. Th₂ cells produce cytokines such as IL-4 and IL-5, which can act indirectly via B cells, mast cells and eosinophils to mediate the asthma phenotype. Alternatively, IL-4 and IL-13 may act directly on the airway. Th₂ lymphocyte inflammation in asthma predisposes subjects to B cell and IgE-mediated airway inflammation. IgE binds to receptors on the surface of a variety of effector cells causing them to release a variety of mediators that promote airway hyperresponsiveness, mucus secretion and increased vascular permeability. Several strategies for decreasing IgE have been developed as a possible treatment for asthma. For example, anti-IgE monoclonal antibodies such as rhuMAb-E25 and CGP 56901 block binding of IgE to its high-affinity receptor and have been shown to reduce IgE levels in humans without causing anaphylaxis. IgE levels must be nearly completely suppressed. Recent clinical studies in subjects with asthma have shown that rhuMAb-E25 attenuates both the early and late phase responses to inhaled allergen, and reduces the associated increase in eosinophils in induced sputum. rhuMAb-E25 is well tolerated and has shown promising results in improving symptoms and lung function in patients with moderate to severe asthma. Other strategies for decreasing IgE levels include interferon γ, IL-4 antibodies, IL-4 receptor antibodies and soluble IL-4 receptors.     

Airway hyperresponsiveness: a story of mice and men and cytokines

Bronchial hyperresponsiveness (BHR) is an essential part of the definition of asthma. Although our understanding of the allergic inflammatory and immunologic mechanisms of asthma have markedly increased, the mechanism of BHR remains to be elucidated. Increased BHR is associated temporally with exposure to allergens, certain respiratory viruses, pollutants such as ozone, and certain occupational chemicals. An important research use of determining the degree of BHR to direct and indirect challenge is to determine the efficacy of pharmacologic and immunodulatory agents. Beta-adrenergic agents inhibit BHR and certain genetic polymorphisms of the beta-adrenergic receptor are associated with increased BHR. When beta-adrenergic receptors are blocked, sensitivity to allergens is markedly increased in patients with asthma and animal models of asthma. Allergen challenge and clinical asthma are associated with synthesis and release of pro-inflammatory cytokines such as IL-1 and TNF-alpha which have been shown to decrease the response to beta-agonists and increased the reactivity to methacholine and the airways neutrophils and alveolar macrophages. The Th2 cytokine IL-13 is increased in the airways of asthmatics and increases BHR in normal unsensitized animals. The mechanisms of this effect of IL-13 are being intensively investigated. Our group has shown that IL-13 induced BHR persisted for at least 7 days and the soluble receptor IL-13R2alpha protected against their BHR. Other investigators have demonstrated that IL-13 is necessary and sufficient for the induction of BHR and that eosinophilic airway inflammation in the absence of IL-13 fails to induce BHR. These studies indicate that treatment of human asthma with antagonists of IL-13 may be very effective.     

Blockade of interleukin-13-mediated cell activation by a novel inhibitory antibody to human IL-13 receptor alpha1

Interleukin-13 (IL-13) is a cytokine with a crucial role in the development of allergic asthma. The IL-13 receptor shares the IL-4Ralpha subunit with the IL-4R system, but contains as a specific component the IL-13Ralpha1 chain. Blocking signal release by IL-13 without affecting IL-4 function is a potentially interesting therapeutical option for the treatment of asthma. Employing genetic immunization, we generated a set of novel monoclonal antibodies to the IL-13Ralpha1 receptor that proved very specific and efficient inhibitors of human IL-13 activity. Receptor binding antibodies were identified by their specific reactivity with both human monocytes and a murine pro-B cell line overexpressing human IL-13Ralpha1 by flow cytometry and cell ELISA. A luciferase reporter cell system based on STAT6-mediated promoter activation in murine Ba/F3 cells was employed to screen the antibodies for IL-13 antagonistic properties. Inhibitory antibody effects were quantified by interference with IL-13-dependent proliferation of TF-1 cells. The capability of blocking IL-13-driven responses of primary, inflammation-relevant cells was tested by Western blot analysis of STAT6 tyrosine phosphorylation and expression of 15-lipoxygenase in monocytes from fresh blood. The most potent inhibitory antibody identified, GM1E7, inhibited IL-13-driven gene activation and cell proliferation in immune cell lines with IC(50) values in the low nanomolar range. Both short-term (STAT6 activation) and long-term (15-LO induction) responses of primary human blood cells to IL-13 were almost entirely blocked, whereas IL-4 effects remained virtually unaffected. GM1E7 is superior to available agents interfering with IL-13 activity in terms of specificity and efficiency and offers potential novel therapeutic perspectives for the treatment of allergic asthma.     

Induction of Interleukin-4 and Interleukin-5 Expression in Mast Cells Is Inhibited by Glucocorticoids

Inflammation in asthma and other allergic diseases is characterized by excessive production of immunoglobulin E (IgE) and the influx of leukocytes, especially eosinophils. Interleukin 4 (IL-4) and IL-5 are essential for IgE production and eosinophilia, respectively, and are produced by mast cells in allergic conditions, for which glucocorticoids are widely used therapeutically. We assessed the effect of glucocorticoids on IL-4 and IL-5 mRNA production by the RBL-2H3 cell line, an analog of mucosal mast cells. IL-4 and IL-5 mRNAs were induced by an antigen that is used to cross-link receptor bound IgE, by calcium ionophore, or by ionophore with phorbol ester and were markedly inhibited by dexamethasone. In cells activated with ionophore and phorbol ester, 10⁻⁶ M dexamethasone reduced the IL-4 and IL-5 mRNA levels to only 12.8 and 5.7%, respectively, of those in cells without dexamethasone, and 10⁻⁹ M dexamethasone caused reductions to 27 and 56%, respectively. Hydrocortisone at 10⁻⁶ and 10⁻⁷ M almost completely inhibited IL-4 and IL-5 mRNA production. Dexamethasone was markedly inhibitory even if it was added after the cells were activated, provided that it was present in the cultures for at least 1.5 h. These studies indicate that the expression of IL-4 and IL-5 mRNAs by mast cells is highly sensitive to glucocorticoids. The data suggest that these inhibitory effects may contribute to the clinical efficacy of glucocorticoids in the therapy of allergic diseases.     

Interleukin-10-secreting "regulatory" T cells induced by glucocorticoids and beta2-agonists

Greater clinical benefit in controlling the symptoms of asthma is frequently observed through combining moderate doses of inhaled glucocorticoids together with long-acting beta(2)-agonists, as compared with increasing glucocorticoid dosage alone. To address in vitro whether glucocorticoids plus beta(2)-agonists, compared with glucocorticoids alone, have greater inhibitory activity on CD4+ T cell responses to allergen, peripheral blood CD4+ T cell responses to allergen were compared in the presence or absence of the glucocorticoid fluticasone proprionate and the short- and long-acting beta(2)-agonists salbutamol and salmeterol, respectively. Fluticasone proprionate inhibited interleukin (IL)-5 and IL-13 and enhanced IL-10 synthesis in allergen-stimulated cultures in a concentration-dependent manner. Salmeterol, but not salbutamol, inhibited IL-5 and IL-13 and enhanced IL-10 synthesis in these cultures. When used in combination the two drugs demonstrated an additive effect on this pattern of cytokine production. Allergen-specific T cell lines induced in the presence of salmeterol and fluticasone proprionate inhibited IL-5 and IL-13 production by allergen-specific Th2 cell lines in an IL-10-dependent manner. Thus fluticasone proprionate and salmeterol increased IL-10 and reduced Th2 cytokine synthesis additively in allergen stimulated human CD4+ T cells.     

The Molecular Mechanism of Human Resistance to HIV-1 Infectionin Persistently Infected Individuals—A Review,Hypothesis and Implications

Resistance to HIV-1 infection in Europeans is associated with a mutation in the gene that codes for the CCR5 protein that is present in Th2 cells and serves as a coreceptor for HIV-1 R5 strain. A deletion of 32 amino acids from the cytokine receptor prevents infection. This mutation prevails in Europeans and is absent in Africans. However, duplication of a gene that codes for a chemokine that binds to the CCR5 was discovered in Africans (mean gene copy 6 while in non-Africans the mean gene copy is 3). Higher expression of these genes protects T cells against HIV-1 infection in vitro. It should be noted that resistance to HIV-1 R5 variant does not protect against HIV-1 R4 variant. It was reported that a minority of highly HIV-1 exposed African professional sex workers (APSW) were resistant to the virus infection during a 10 years period. Recently, the analysis of the cytokines in the serum of the persistently infected seronegative women revealed that the latter hypo-expresses the cytokine IL-4. Since the molecular events during HIV-1 infection are associated with a marked increase in the levels of IL-4 and IgE in the sera of the infected individuals, it suggests that AIDS is an allergy. Thus, a very low level of IL-4 production may abrogate the virus infection. Studies on the human IL-4 gene revealed that together with the IL-4 mRNA a spliced variant with a deletion of exon 2 is synthesized. The latter is a natural antagonist of IL-4 and when expressed in an individual at a level higher than IL-4, the person will resist a microbial infection (e.g. Mycobacterium tuberculosis) or asthma. The present hypothesis suggests that the HIV-1 resistant APSWs produce more IL-4 delta 2 molecules than IL-4 molecules. The binding of IL–4 delta 2 to IL-4 receptors on T and B cells prevents their functions and the infection by HIV-1. The implications of these studies are that treatment of HIV-1 infected people with drugs that will block the IL-4 receptors will stop HIV-1 infections and the determination of the levels of IL-4 and IL-4 delta 2 in the sera of HIV-1+ patients will enable to identify the individuals that have a natural resistance to HIV-l/AIDS and those who need treatments.     

Genetic manipulation of beta-adrenergic signalling in heart failure.

Heart failure (HF) represents one of the leading causes for hospitalization in developed nations. Despite advances in the management of coronary artery disease, no significant improvements in prognosis have been achieved for HF over the last several decades. Heart failure itself represents a final common endpoint for several disease entities, including hypertension, coronary artery disease, and cardiomyopathy. However, certain biochemical features remain common to the failing myocardium. Foremost amongst these are alterations in the beta-adrenergic receptor signalling cascade. Recent advances in transgenic and gene therapy techniques have presented novel therapeutic strategies for the management of HF via enhancement of beta-adrenergic signalling. In this review, we will discuss the biochemical changes that accompany HF as well as corresponding therapeutic strategies. We will then review the evidence from transgenic mouse work supporting the use of adrenergic receptor augmentation in the failing heart and more recent in vivo applications of gene therapy directed at reversing or preventing HF.     

CD antigens 2001

The most recent Human Leucocyte Differentiation Antigen Workshop ("HLDA7") took place in 2000 in Harrogate, UK and the proceedings are about to be published (Leucocyte Typing VII). New Sections were introduced in this Workship (Dendritic cells, Stem/progenitor cells, Erythroid cells and Carbohydrate Structures) and monoclonal antibodies were selected for which at least some molecular data were already available (to avoid "blind" screening of reagents against known specificities). A total of more than 80 new CD specificities were established (previously the average was less than 30 new CD specificities per Workshop) and these are listed in this article. There is already evidence for the existence of many new leucocyte surface molecules for study at the next HLDA Workshop (in Adelaide in 2004), and we have listed in this article a number of such potential CD candidates (identified following the production of monoclonal antibodies or via gene cloning). There are also today an increasing number of lineage- and/or stage-restricted leucocyte-associated molecules localised within the cell cytoplasm (or nucleus): they will certainly prove of intense in the future for many laboratories studying human haematopoietic cells (regardless of whether a new "intracellular CD" categorisation scheme is devised for such molecules).     

Molecular therapy versus standard treatment in allergy (Review)

The increasing knowledge concerning pathomechanism of allergy creates new perspectives for treatment. Standard methods currently applied in allergy act multidirectional, usually being crude and unselective. Moreover, such therapy does not eliminate the cause of hyperresponse reaction and often fails to restore the immunological balance. It is also noteworthy that the conventional therapy frequently affects different tissues not directly involved in allergic reaction and thus it may exert numerous side effects. The hypersensitivity was found to be related to some cytokines network abnormalities. Among cytokines, there are a few, well-recognized factors e.g., interleukin-4 (IL-4), IL-5 and IL-13, which play a pivotal role in allergy. Thus, the major goal for causal allergy treatment should be restoration of the balance in cytokine-mediated regulation of allergen-driven immunological response. It could be achieved by administration of missing cytokines, e.g., interferon-gamma (IFN-gamma) and/or down regulation of excessive one, e.g., IL-4, IL-13. Such a therapy, directed towards only specific, allergy-involved molecules, should not affect the other by-standing particles or reactions. Obviously, a good target for this kind of treatment could be immunoglobulin E (IgE) that is causally related to anaphylactic response. Furthermore, especially promising objectives for molecular therapy seem to be some cytokine receptors and signal transduction pathways and some adhesion molecules. The most recent therapeutical strategies attempting to restore immunological balance in allergy are presented. They include, among others, anti-cytokine antibodies, their soluble receptors, antisense oligonucleotides and small interfering RNA. Although many of these topical methods are still in the trial phase, we suppose they will become a clinical reality in the near future.     

Switching between biologics in severe asthma patients. When the first choice is not proven to be the best

During the last decades, new treatments targeting disease mechanisms referred as biologics have been introduced in the therapy of asthma and currently, five monoclonal antibodies have been approved. Although these therapeutic agents have been formulated to target specific asthma endotypes, it is often difficult for the treating physician to identify which patient is the best candidate for each one of these specific treatments especially in the clinical scenario of a patient in whom clinical characteristics overlap between different endotypes, allowing the selection of more than one biologic agent. As no head-to-head comparisons between these biologics have been attempted, there is no evidence on the superiority of one biologic agent over the other. Furthermore, a physician's first therapeutic decision, no matter how carefully has been made, may often result in suboptimal clinical response and drug discontinuation, indicating the need for switching to a different biologic. In this short review, we discuss the available evidence regarding the switching between biologics in patients with severe asthma and we propose a simple algorithm on switching possibilities in case that the physicians’ initial choice is proven not to be the best.     

Interleukin-20 Promotes Airway Remodeling in Asthma

Previous studies have demonstrated that interleukin-20 (IL-20) is a pro-inflammatory cytokine, and it has been implicated in psoriasis, lupus nephritis, rheumatoid arthritis, atherosclerosis, and ulcerative colitis. Little is known about the effects of IL-20 in airway remodeling in asthma. The aim of our study was to demonstrate the function of IL-20 in airway remodeling in asthma. To identify the expression of IL-20 and its receptor, IL-20R1/IL-20R2, in the airway epithelium in bronchial tissues, bronchial biopsy specimens were collected from patients and mice with asthma and healthy subjects and stained with specific antibodies. To characterize the effects of IL-20 in asthmatic airway remodeling, we silenced and stimulated IL-20 in cell lines isolated from mice by shRNA and recombinant protein approaches, respectively, and detected the expression of α-SMA and FN-1 by Western blot analysis. First, overexpression of IL-20 and its receptor, IL-20R1/IL-20R2, was detected in the airway epithelium collected from patients and mice with asthma. Second, IL-20 increased the expression of fibronectin-1 and α-SMA, and silencing of IL-20 in mouse lung epithelial (MLE)-12 cells decreased the expression of fibronectin-1 and α-SMA. IL-20 may be a critical cytokine in airway remodeling in asthma. This study indicates that targeting IL-20 and/or its receptors may be a new therapeutic strategy for asthma.     

Interleukin-18 expression,CD8+ T cells,and eosinophils in lungs of nonsmokers with fatal asthma

BackgroundThe process of airway inflammation in the lungs of nonsmokers who die of asthma (fatal asthma) has not been reported in detail.ObjectiveTo examine nonsmokers who had died of asthma to exclude chronic obstructive pulmonary disease and investigate pulmonary inflammatory cells and the expression of interleukin-18 (IL-18) and its receptor in lung tissues compared with those in patients with well-controlled mild asthma and nonsmokers.MethodsLung tissues were obtained at autopsy examination from 12 nonsmokers with fatal asthma, excluding cases of chronic obstructive pulmonary disease, and from 5 nonsmokers with well-controlled mild asthma and 10 nonsmokers who had undergone surgical resection for lung cancer. Pulmonary inflammatory cells were examined and the expression of the proinflammatory cytokine IL-18 and its receptor in the lungs was evaluated.ResultsThe numbers of eosinophils and lymphocytes, but not basophils or macrophages, were significantly increased in the lungs of patients with fatal asthma compared with the other 2 groups. The lung neutrophil count did not differ significantly between the fatal and mild asthma groups but was significantly higher in the fatal asthma group than in nonsmokers. CD8⁺ T cells, but not CD4⁺ T cells, were significantly increased in the lungs of the fatal asthma group compared with the other 2 groups. IL-18 protein and IL-18 receptor were strongly expressed in the lungs in the fatal asthma group.ConclusionCaspase-1 inhibitors, anti–IL-18 antibodies, anti–IL-18 receptor antibodies, IL-18 binding protein, or inhibitors of genes downstream of the IL-18 signal transduction pathway may be of clinical benefit for the treatment of patients with severe asthma.     

Airway hyperresponsiveness

Bronchial hyperresponsiveness (BHR) is an essential part of the definition of asthma. Although our understanding of the allergic inflammatory and immunologic mechanisms of asthma have markedly increased, the mechanism of BHR remains to be elucidated. Increased BHR is associated temporally with exposure to allergens, certain respiratory viruses, pollutants such as ozone, and certain occupational chemicals. An important research use of determining the degree of BHR to direct and indirect challenge is to determine the efficacy of pharmacologic and immunodulatory agents. Beta-adrenergic agents inhibit BHR and certain genetic polymorphisms of the beta-adrenergic receptor are associated with increased BHR. When β-adrenergic receptors are blocked, sensitivity to allergens is markedly increased in patients with asthma and animal models of asthma. Allergen challenge and clinical asthma are associated with synthesis and release of pro-inflammatory cytokines such as IL-1 and TNF-α which have been shown to decrease the response to β-agonists and increased the reactivity to methacholine and the airways neutrophils and alveolar macrophages. The Th2 cytokine IL-13 is increased in the airways of asthmatics and increases BHR in normal unsensitized animals. The mechanisms of this effect of IL-13 are being intensively investigated. Our group has shown that IL-13 induced BHR persisted for at least 7 days and the soluble receptor IL-13R2α protected against their BHR. Other investigators have demonstrated that IL-13 is necessary and sufficient for the induction of BHR and that eosinophilic airway inflammation in the absence of IL-13 fails to induce BHR. These studies indicate that treatment of human asthma with antagonists of IL-13 may be very effective.