The first experimental evidence that environmental tobacco smoke (ETS) can exacerbate allergies was published in the July issue of the Journal of Allergy and Clinical Immunology.
David Diaz-Sanchez and colleagues of the University of California, CA, USA have found that ETS, or second-hand smoke, could predispose allergic patients to more severe responses with allergens. A total of 19 nonsmoking volunteers who are allergic to ragweed participated in the study. Nasal lavage (rinse) fluid was collected from each participant before they were exposed to either tobacco smoke or clean air for 2 h in controlled chambers. Participants were then immediately and randomly exposed to either ragweed allergen or a placebo (saline). Nasal lavage fluid was collected again on days 1, 4 and 7 after the treatments and analyzed for immunoglobulin (Ig)E and histamine levels. IgE is the antibody produced in response to allergens, such as ragweed pollens. IgE interacts with receptors on immune cells (basophils and mast cells) causing these cells to release histamine. Histamine stimulates the widening of blood vessels and leaking of fluid and proteins from blood to surrounding tissues, leading to local tissue inflammation.
In patients exposed to ETS/ragweed, the level of IgE on day 4 was 16.6-times higher than in those exposed to clean air/ragweed. Histamine level in nasal fluid was also 3.3-times higher in patients exposed to ETS/ragweed compared with clean air/ragweed. ETS-exposed people also had an increase in ‘allergic-response’ cytokines, such as interleukin (IL)-4, -5 and -13. These cytokines are small protein molecules produced by various immune cells in response to allergens.
From the results, the researchers hypothesized that tobacco smoke could interact with allergens, alter the immune response and promote changes associated with allergic airway disease and advised that allergic nonsmokers should avoid second-hand smoke.
Inhaling fluticasone does not help cystic fibrosis patients
Not only does inhaled fluticasone cause adverse effects and put financial burden on cystic fibrosis (CF) patients, but it does not improve the disease condition, stated a research group of the Royal Brompton & Harefield Hospital, UK, last month in the American Journal of Respiratory and Critical Care Medicine.
Fluticasone propionate is a corticosteroid prescribed commonly to asthma and allergic rhinitis patients. It is available commercially under various brand names, such as Flixonase® (Allen & Hanburys) and Flonase® (GlaxoSmithKline). It is known to inhibit a number of cells, such as mast cells and neutrophils, thus preventing inflammatory reactions. However, the drug only takes effect several days after inhalation and the exact mechanism for immediate relief in breathing difficulty is not well understood, despite its wide use in CF.
The research team chose two groups of CF patients aged older than 6 years and who had used corticosteroids for more than 3 months prior to the study. Each group inhaled either fluticasone or a placebo for 6 months, over which period lung function, increase of disease severity and antibiotic and bronchodilator use were monitored. No difference was found when fluticasone was used in comparison with the placebo.
The authors confirmed that stopping using corticosteroids is safe for patients with CF. It can help reduce drug burden on the patients as well as save money.
“Long-term use (of corticosteroids) is precluded by unacceptable side effects”, said the research team leader, Balfour-Lynn. The conclusion from six randomized controlled trials reveals that “there was no evidence…to support the practice of prescribing inhaled steroids in cystic fibrosis”, he added.
More than 52% of the patients were on high doses of inhaled corticosteroids, which can lead to adrenal suppression. The drug can also affect the growth of pediatric patients. The scientists, however, did not urge the withdrawal of corticosteroids in CF and advised clinicians to judge patient needs on a case-by-case basis.
Asthma treatment: right drug for right gene
A total of 13% of asthma patients may be taking an ineffective drug for the condition owing to their genetic background. The finding was published in the journal Thorax in June.
Asthma is a condition in which the patient’s airway is narrowed resulting in breathing difficulties. Salmeterol is a common bronchodilator of the β2-agonist type, which stimulates β2-receptors on the airway smooth muscle cells, causing these cells to relax and open the airway.
Scientists from the University of Dundee, UK, studied the effect of salmeterol on 546 young patients for over 6 months. While the drug was effective in most patients, a group with a specific genetic variation suffered from asthma attacks almost twice as frequently as the rest.
“It was apparent that some patients with asthma could be failing to respond to inhaled salmeterol, but we have identified a likely cause for this that is linked to this genetic status”, said one of the researchers, Somnath Mukhopadhyay.
The genetic variation, called Arg/Arg16, occurs in the β2-adrenoceptor gene of approximately 13% of studied patients, making the patients ‘inert’ with salmeterol. The exact mechanism is yet to be defined.
Various treatments are used by the 5.2 million asthma patients currently in the UK. It is important that the patients monitor the effect of salmeterol and switch to an alternative if the drug appears ineffective, rather than using additional treatments.
The findings of this study have prompted the question of whether genetic testing is necessary before prescribing asthma treatment. It also reinforces the importance of genetic information in choosing the best drugs for each individual.
Calming the battle of oneself
Rheumatoid arthritis (RA) may be treated by inhibiting the inflammatory effects of neutrophils, Jamel El-Benna and colleagues from INSERM, Paris, France have reported in the July issue of the Journal of Clinical Investigation.
RA is a chronic autoimmune disorder, in which the immune system attacks the joints, causing inflammation, pain and potential loss of mobility. This involves many cell types, one of which is the neutrophil. Being motile, neutrophils gather quickly at the inflammatory site and release a large amount of superoxide and other reactive oxygen species (ROS), which are designed to kill pathogens but, in this case, cause severe damage to the host.
The research team discovered that mitogen-activated protein kinase (MAPK) inhibitors could prevent the production of ROS. MAPK inhibitors bind to the MAPK region of neutrophil NADPH oxidase, an enzyme responsible for ROS production. By doing so, MAPK inhibitors block the effect of cytokines (granulocyte–macrophage colony-stimulating factor and tumor-necrosis factor-α) that can otherwise activate NADPH oxidase.
The work has elucidated the pathways that activate the NADPH oxidase of neutrophils, hence revealing possible targets for the development of RA drugs.
Re-release Tysabri® for relapsing multiple sclerosis
Following its withdrawal over a year ago, Tysabri® is now back on the market. Biogen Iden (MA, USA) has received approval to circulate the drug once more – this time under a special distribution program.
Tysabri was first available commercially in November 2004. Soon after that, a rare but serious viral infection of the brain, progressive multifocal leukoencephalopathy (PML), was seen in three patients, two of whom died. The US FDA postponed all related clinical trials last year, examined patients in previous trials and started a subsequent trial at the beginning of this year. This trial reconfirmed that the drug is safe.
Tysabri is used in multiple sclerosis patients where other drugs fail to lessen the disease. It is now regulated strictly and all patients are required to be registered and monitored on a regular basis in order to identify and investigate any adverse effects it may cause. The connection between previous PML cases and Tysabri remains unknown.
Tysabri is a monoclonal antibody-based drug and should not be used together with other drugs acting on the immune system.
Tricking the host immune system in xenotransplantation
Grafting tissues from one animal species to another proves hugely difficult owing to rejection by the host immune system. However, scientists at the Weizmann Institute of Science, Israel might have found a way around it.
Last year, a research team led by Yair Reisner published their findings in the Proceedings of the National Academies of Science USA. The authors transplanted various embryonic tissues of various gestation ages from pigs into mice. They found that, for pancreas tissue, the optimal age was from embryonic day (E)42 to E56, before which the transplant would become a tumor and after which the host would reject the transplant fiercely.
Last month, Reisner’s group successfully transplanted E42 pancreas tissue from pig embryo into diabetic, immunodeficient mice that carried human immune cells. The team confirmed that this transplant developed well, was able to secret insulin and maintain normal blood glucose level in these diabetic mice and was better tolerated by the human immune cells than E56 or later pancreas tissues. When transplanted into immunocompetent mice that were treated with an immunosuppression protocol, E42 pig pancreas tissue also developed and functioned well for a prolonged period. The work was published in the June 2006 issue of the journal Public Library of Science Medicine.
“The results of this study warrant further, preclinical research on primate models”, commented Reisner. This study moves us a step closer to a diabetes therapy without the need of injected insulin.