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Archives: Medical Journal Reviews

Medical Journal Review

Posted: October 2007

Reviewed by Prof. Richard F. Lockey, MD, WAO Web Editor-in-Chief and Guest Reviewer Gary Hellermann, PhD

1.  IL-15 constrains mast cell-dependent antibacterial defenses by suppressing chymase activities.
Using a mouse model of bacterial sepsis, the authors found that IL-15 deficiency improves survival. IL-15 enhances the immune response by activating T cells, thymocytes, B cells and natural killer cells. In this study, IL-15 inhibits transcription of mast cell protease-2 (chymase), an enzyme that breaks down a cellular protein to yield neutrophil-activating protein-2 (NAP-2), which recruits neutrophils to the infection site. The protease-2 activity is regulated by IL-15, and deletion of IL-15 in mice results in more rapid bacterial killing and improves survival in this experimental sepsis model. Editor’s comment: Inhibiting IL-15 production within mast cells may improve sepsis survival in humans. Orinska Z et al. Nature Med. 2007; 13:927-934. (Editorial: Ward PA, 13:903)

2.  Allergen Immunotherapy:  A Practice Parameter Second Update. 
The September supplement to JACI is the second allergen immunotherapy practice parameter document. It includes 352 references and thoroughly covers the science of various forms of allergen immunotherapy. Following the introduction, subjects such as mechanisms, available allergen extracts, efficacy, safety, patient selection, schedules and doses, and other aspects of treatment are thoroughly covered. Each section starts out with a summary statement followed by its scientific rationale. Editor’s comment: This practice parameter is a must read for every allergist who prescribes allergen immunotherapy.  Cox, et al. JACI 2007; 120:S25.

3.  Anti-inflammatory effects of high-dose inhaled fluticasone (F) versus oral prednisone (P) in moderate asthma exacerbations.
A randomized clinical trial. From a group of 45 asthmatic patients treated for moderate asthma in the Emergency Room, 19 received F plus P placebo while 20 received P plus F placebo. Smokers and those with serious chronic illness or treated with oral or i.v. corticosteroids within four weeks before the study were excluded. F was delivered by inhaler at a metered dose of 4000 mg/day (16 puffs) and P was given as one pill, 30 mg/day. Symptoms improved in both groups with no difference in PEF, FEV1 or sputum eosinophil count after 24 hours. Inhaled F versus P produced more rapid initial improvement in some symptoms. Editor’s comment: The results support the idea that high-dose inhaled F may be as effective as moderate doses of P to treat asthma exacerbations. Belda J et al. Eur Resp J 2007 [Epub Aug. 9 ahead of print].

4.  A study to evaluate safety and efficacy of mepolizumab in patients with moderate persistent asthma.
IL-5 is involved in recruitment, activation and survival of eosinophils, the accumulation of which is associated with AHR and production of inflammatory mediators in asthmatics. This multicenter, randomized, placebo-controlled study sought to determine whether administration of the humanized monoclonal IL-5 antibody, mepolizumab (Mep), to a group of asthmatic patients improved symptom scores, sputum eosinophilia and QOL. The subjects were 18-55 years of age with FEV1 ³50% but £80% of predicted and managed by inhaled corticosteroids and beta agonists. Participants were drawn from 55 centers in France, Germany, the Netherlands, UK and US, and 362 patients were randomized into three groups: Mep 250 mg, Mep 750 mg or placebo. Treatments (i.v. injection) were done at baseline (visit three) and twice more at four-week intervals. Efficacy was measured four weeks after the final dose with an eight-week follow-up. Mep injection reduced blood and sputum eosinophils but other outcome measurements were not significantly different from placebo. Editor’s comment: While anti-IL-5 therapy for asthma theoretically should be effective, the clinical results are disappointing. Flood-Page P et al. Am J Resp Crit Care Med 2007; [Epub Sept. 13 ahead of print].

5.  RSV decreases p53 protein to prolong survival of airway epithelial cells.
P53 is a tumor suppressor protein that induces expression of genes for apoptosis and blockade of the cell cycle. When p53 expression is low, as in cancer cells, they do not die. In mice, p53 levels are reduced by murine double minute protein 2 (Mdm2), which causes proteolytic breakdown of p53. RSV infection can increase Mdm2 levels by phosphorylation, and this causes a corresponding decrease in p53 protein and expression of apoptosis genes. The RSV-infected epithelial cells survive longer, but they do not produce more virus. Here, mice were treated with Nutlin-3, an inhibitor of Mdm2, then infected with RSV, and it was found that p53 levels increase and epithelial cells undergo more apoptosis than controls. However, the increased p53 also causes an increase in viral replication and decrease in IL-6. Editor’s comment: This paper contributes to the understanding of the complex interaction between RSV and the immune system and may lead the way to the development of new antivirals. Groskreutz DJ et al. J Immunol 2007; 179:2741-2747.

6. Pharmacologic rationale for treating allergic and non-allergic rhinitis. 
This is an excellent review in the JACI on the subject of the drug treatment of allergic and non-allergic rhinitis. The paper reviews various classifications of rhinitis and algorithms for pharmacologic treatment of allergic and non-allergic rhinitis. It also reviews controversial treatment such as use of intranasal saline and capsaicin. Author's comment:  Excellent review, everybody who treats rhinitis should read it.  Greiner, et al. JACI 2006;118:985.

7.  Extracellular ATP triggers and maintains asthmatic airway inflammation by activating dendritic cells.
ATP can be released from damaged lung cells during stress and acts upon cells of the immune system via the purine receptors, P2X and P2Y. This paper investigates ATP’s potential role in asthma using human bronchoalveolar lavage fluid and a mouse model of allergic asthma. Allergen challenge increases ATP in the lungs accompanied by overexpression of the Th2 cytokines, IL-4, -5 and -13. When ATP is enzymatically neutralized or when the P2 receptors are blocked, airway inflammation is reduced. The authors found that ATP induces expression of a dendritic cell chemoattractant and also directly stimulates maturation of and cytokine production by dendritic cells. Editor’s comment: Suppressing purine receptor signaling might be a useful adjunct to asthma therapy. Idzko M et al. Nature Med 2007; 13:913-919.

8.  Effects of systemic glucocorticosteroids (GCS) in patients with severe community-acquired pneumonia (CAP).
The goal of this investigation was to determine the efficacy of GCS in reducing the mortality from CAP. In this retrospective study, 308 elderly patients hospitalized with CAP were evaluated and of that number, 70 had received antibiotics and systemic GCS (equivalent to methylprednisone ≥24 mg/day or prednisone ≥ 30 mg/day). The others received antibiotics alone. The number of deaths among those treated with GCS was significantly reduced compared to those not receiving GCS. Editor’s Comment: While this report showed beneficial effects from systemic GCS in elderly patients with CAP, additional studies are needed. Garcia-Vidal C et al. Eur Resp J 2007; [Epub Aug. 9 ahead of print].

9.  Dominant-negative mutations in the DNA-binding domain of STAT3 cause hyper-IgE syndrome.
Hyper-IgE syndrome (HIES) is represented by an array of symptoms including skin abscesses, cyst-forming pneumonia, skeletal and dental abnormalities and elevated serum IgE levels. The presence of multi-system effects in HIES suggests that a factor affecting expression of a number of genes might be defective. This study reports that single amino acid changes in the DNA-binding domain of STAT3 are responsible for HIES in 8 out of 15 unrelated non-familial patients. Parents and siblings of the HIES patients as well as a panel of 1000 unrelated healthy controls have the normal STAT3 DNA sequence. The mutant STAT3 is dominant over the normal STAT3 and causes defective responses to IL-6 and IL-10 and reduces DNA binding. Editor’s Comment: The complexity of HIES is underscored by the observation that there is no difference in overt symptoms between HIES patients with versus those without the STAT3 mutations. Minegishi Y et al. Nature 2007; 448:1058-1062.

10.  IgE-antibody-dependent immunotherapy of solid tumors: Cytotoxic and phagocytic mechanisms of eradication of ovarian cancer cells.
The use of tumor-specific Abs to target cancer cells for destruction is a promising avenue of research, and this report demonstrates that the IgE isotype may be more effective than IgG in treating sarcomas. Human ovarian cancer cells in culture were exposed to human peripheral blood monocytes (PBMCs) in combination with IgE Ab against folate-binding protein, an ovarian cancer-specific marker. Three-color flow cytometry analysis shows that Ab-activated monocytes kill tumor cells by both cytotoxic means and phagocytosis. In vivo experiments utilized nude mice injected with ovarian cancer cells with or without PBMCs and Ab. IgE Ab treatment results in enhanced cancer cell killing in vitro and increased survival of mice injected i.p. with ovarian cancer cells. The report also elucidates the mechanism of tumor cell killing by monocytes and demonstrates that a tumor-specific IgE Ab can direct eosinophils to kill ovarian cancer cells. Editor’s comment: This report offers hope for an improved treatment strategy utilizing tumor-specific IgE Abs. Karagiannis SN et al. J Immunol 2007; 179:2832-2843.

11.  IL-13 regulates cilia loss and foxj1 expression in human airway epithelium.
Defects in mucociliary clearance in the lung lead to mucus plugging and impaired clearance of microbes and particulates. These defects can result from RSV infection which causes loss of ciliated epithelial cells and excess mucus production in RSV-infected infants and asthmatics. This report examines the mechanism of ciliary loss and repair using cultured human airway epithelium. Treatment of cells with IL-13 results in 65-90% loss of ciliated cells and downregulation of the transcription factor, foxj1, which is necessary for cilia formation. The fact that IL-13 is elevated in asthma and respiratory infections suggests that it may be the instigator of ciliated epithelial cell loss. Editor’s Comment: An additional observation is the potential trans-differentiation of ciliated epithelial cells to mucous cells, which supports the idea of cellular plasticity in airway epithelium. Gomperts BN et al. Am J Resp Cell Mol Biol 2007; 37:339-346.