Medical Health

Activating a protein found on some immune cells seems to halt the cells’ typical job of spewing out substances that launch allergic reactions, a study by Johns Hopkins researchers suggests. The findings could eventually lead to new treatments for allergic reactions ranging from annoying bouts of hay fever to deadly asthma attacks.

Previous studies by Bruce Bochner and his colleagues at the Johns Hopkins Asthma and Allergy Center had zeroed in on the protein, Siglec-8, as an important player in allergic reactions. This protein is found on the surfaces of some types of immune cells, namely eosinophils, basophils and mast cells, which have diverse but cooperative roles in normal immune function and allergic diseases. Eosinophils directly combat foreign invaders, such as parasites. Basophils and mast cells store and release substances such as histamine, prostaglandins and cytokines, which signal other immune system cells to ready for battle.

When functioning correctly, these cells are a valuable aid to keeping the body healthy and infection-free. However, in allergic reactions and asthma attacks, the cells unleash an overwhelming response that typically harms the body more than it helps.

The researchers found in previous studies that when they activated Siglec-8 on the surface of eosinophils, the cells promptly died. Expecting the same suicidal response in mast cells, the scientists tested their theory in a new study on human mast cells and mast-cell-containing tissues.

Using mast cells grown in a lab, the researchers used antibodies to activate Siglec-8. "We were surprised to see that these cells just sat there happily in their petri dishes and lived on," says Bochner, director of the Division of Allergy and Clinical Immunology at the Johns Hopkins University School of Medicine.

With their initial theory disproven, Bochner and his colleagues suspected that Siglec-8 might be slowing down other cellular processes based on the protein’s distinctive structure. To investigate what else Siglec-8 might inhibit, the scientists activated the protein in mast cells once again with antibodies. Then, they attempted to trigger an allergic response from these cells.

Normally, mast cells respond with an outpouring of histamine, prostaglandins and other substances that spur allergic reactions in other cells. However, Bochner and his colleagues found that cells with activated Siglec-8 released less than half the typical amount of these substances.

Extending their experiment from cells to whole tissues, Bochner and his colleagues used antibodies to activate mast cells’ Siglec-8 in small pieces of human lung saved from autopsies. When the researchers triggered the cells to release their payloads-an act that typically causes airways to sharply constrict-the contractions were about 25 percent weaker than in lung tissue where the mast cells’ Siglec-8 wasn’t activated.

The researchers are still unsure exactly how Siglec-8 inhibits mast cells from releasing their immune-triggering chemicals. However, follow-up experiments suggested that activating the protein keeps calcium from moving efficiently into the cells. Mast cells need this calcium signal to release their contents.

Bochner notes that researchers might eventually use these results, published in the February Journal of Allergy and Clinical Immunology, to develop a drug with this same effect. Such a drug would have the dual effect of blocking or reducing allergic reactions by killing eosinophils and preventing mast cells from releasing their substances.

"Both of these effects could make allergic diseases and asthma less severe," he says. "It’s an intriguing approach because there are no drugs that specifically target both these cell types."

Though drugs exist that affect either eosinophils or mast cells, Bochner says developing a single drug that takes aim at both types of cells could be even more effective than existing therapies and may also have a reduced risk of side effects. He and his colleagues are also searching for natural molecules in the body that activate Siglec-8, which could bring researchers a step closer to developing pharmaceuticals that target this protein.

Additional Hopkins researchers who contributed to this paper include Hidenori Yokoi, M.D., Oksoon H. Choi, Ph.D., Walter Hubbard, Ph.D., Hyun-Sil Lee, Ph.D., Brendan J. Canning, Ph.D., Hyun H. Lee, M.D., Seung-Duk Ryu, Ph.D., Stephan von Gunten, Ph.D., Carol A. Bickel, M.S., Sherry A. Hudson, M.S.B., and Donald W. MacGlashan Jr., M.D., Ph.D.

Johns Hopkins Medicine
901 S. Bond St., Ste 550
Baltimore, MD 21231
United States
http://www.hopkinsmedicine.org

New research released has found that babies exposed to secondhand smoke are almost twice as likely to develop allergies to inhaled allergens such as animal hair as infants who are not exposed to tobacco smoke. Children whose parents smoke are almost 50% more likely to be allergic to certain foods. [1]

The findings are based on parental survey responses from more than 4000 families about their children’s allergies and environmental factors to which they were exposed before and after birth. These included parental smoking, pet dander (animal hair and dead skin) and foodstuffs.

One in 12 mothers smoked throughout pregnancy and one in 8 smoked during part of the pregnancy. The researchers found no evidence that smoking while pregnant affected a child’s risk of becoming sensitised to a certain allergen. But there was a dose-response effect for exposure to secondhand smoke during the first weeks of life and markers for sensitisation. Furthermore, the effect of secondhand smoke exposure was stronger among children with non-allergic parents than among those with parents who had allergies.

Amanda Sandford, Research Manager of the health campaigning charity ASH, said:

"This study provides yet more evidence of the need to ensure that babies and young children are not exposed to tobacco smoke. Whilst the development of some allergies may not be fully understood, this research shows that one way of substantially reducing the risk is by banning smoking in the home.

The study adds to the already substantial body of evidence of the harmful impacts of secondhand smoke on children, particularly in the early years of development. [2] Simply restricting smoking to certain rooms does not offer enough protection to infants and families should therefore make every effort to make their homes smokefree to give their children the best possible start in life. "

Notes:

[1] Lannero E et al. Exposure to environmental tobacco smoke and sensitisation in children. Thorax 2007

[2] Going smoke-free. The medical case for clean air in the home, at work and in public places. Royal College of Physicians, London, 2005

http://www.ash.org.uk

A mechanism which can lead to hay fever and other allergic reactions, by preventing the immune system from regulating itself properly, has been discovered by scientists. Researchers hope their finding, published (Thursday 27 December 2007) in the journal PLoS Biology, will allow therapies to be developed that treat allergies by stopping this mechanism.

The new research shows that a gene known as GATA-3 can block the development of regulatory T-cells in the immune system by locking another gene. This gene, FOXP3, is key to regulatory T cells and when it is blocked new regulatory T cells stop being produced.

The scientists, from Imperial College London, the Swiss Institute of Allergy and Asthma Research in Davos, Switzerland, and other international institutions, hope that if they can develop therapies to stop FOXP3 being blocked, they can ensure that regulatory T cells are free to work normally.

Regulatory T cells are believed to be vital for averting allergic reactions in healthy individuals because they keep the other cells in check, suppressing pro-allergic cells known as Th2 cells and stopping the immune system from needlessly attacking the body.

In people with allergies, some types of cells in the immune system, particularly the Th2 cells, wrongly identify a particular allergen, such as pollen, as being dangerous. Whenever the person encounters this allergen again, these cells promote the production of antibodies to attack it, causing an allergic reaction.

Dr Carsten Schmidt-Weber, the principal investigator on the research from the National Heart and Lung Institute at Imperial College London, said: "This finding will help us to understand how healthy individuals are able to tolerate allergens and what we need to do to re-induce tolerance in the immune systems of patients with allergies. We hope that we will soon be able to help not only patients suffering from single allergies, but also those with multiple ones - the atopic patients."

The researchers reached their conclusions by analysing the genes related to regulatory T-cells and analysing how they interacted. They confirmed their findings by using mouse models to show that mice which were genetically engineered to express the GATA-3 gene in all T cells showed dramatic defects in the production of regulatory T-cells.

Dr Schmidt-Weber and his colleague Professor Stephen Durham, also from the National Heart and Lung Institute at Imperial College, hope the new findings will eventually lead to new, more effective treatments for hayfever and other allergies, to be used in combination with existing immunotherapies. They hope such treatments could help prevent hay fever and allergic asthma from reaching epidemic proportions.

This research was funded by the Swiss National Science Foundation, the Ehmann Foundation Chur, the Saurer Foundation Zurich and Swiss Life Zurich.

Imperial College London
http://www.imperial.ac.uk

Allergic-like reactions to gadolinium-containing contrast injections in adults and pediatric patients (those younger than 19 years of age) are rare, according to a recent study conducted by researchers at the University of Michigan Health Systems in Ann Arbor. "When these reactions do occur, most of them are mild," said Jonathan R. Dillman, MD, lead author of the study.

"Over the past few years, the utilization of contrast-enhanced MRI has markedly increased; it’s increased by 65% at our institution over the previous five years," said Dr. Dillman.. This is due, at least in part, to a variety of new applications, such as magnetic resonance angiography (MRA) and abdominopelvic MR imaging," he said. "Consequently, the number of intravenously administered gadolinium-containing contrast material doses over the same time period has significantly increased. Based on the extensive use these intravascular contrast agents, we felt that it was once again time to study their safety profile," he said.

The study included 78,353 gadolinium-containing contrast injections over a five year period. Acute allergic-like reactions occurred following 54 injections. According to the study, 48 reactions involved adults and six occurred in pediatric patients. The study showed that 74% of these reactions were mild, 19% were moderate, and 7% were severe.

"Despite recent concerns that have emerged about the gadolinium-based contrast agents and the development of nephrogenic systemic fibrosis in patients who have severe chronic kidney disease, our study supports the long-held belief that gadolinium based contrast agents can be used safely in both pediatric and adult patients with normal or with only mildly impaired renal function," said Dr. Richard Cohan, co-author of the study. "The risk of allergic-like reactions is exceedingly low (0.07% of administrations in our study), and no fatal reaction occurred at our institution in more than 78,000 intravenous administrations. Patients should feel reassured, based on our results, that the intravenous gadolinium-contrast agents included in our study are quite safe when administered to patients with ample renal function," he said.

The full results of this study appear in the December issue of the American Journal of Roentgenology, published by the American Roentgen Ray Society.

American Roentgen Ray Society
http://www.arrs.org

Perrigo Company (Nasdaq: PRGO; TASE) announced that it has received final approval from the U.S. Food and Drug Administration for its Abbreviated New Drug Application (ANDA) for over-the-counter (OTC) Cetirizine Hydrochloride Tablets, 5 and 10 mg.

The product will be marketed under store brand labels and is comparable to McNeil Consumer Healthcare’s Cetirizine Hydrochloride Tablets, 5 and 10 mg, which will be marketed as Zyrtec(R) Tablets, indicated for allergy and hives relief. According to Wolters Kluwer data, brand sales for the original prescription strength version of the product for the 12 months ending October 2007 were approximately $1.4 billion.

Perrigo Company is a leading global healthcare supplier that develops, manufactures and distributes over-the-counter (OTC) and prescription pharmaceuticals, nutritional products, active pharmaceutical ingredients (API) and consumer products. The Company is the world’s largest manufacturer of OTC pharmaceutical products for the store brand market. The Company’s primary markets and locations of manufacturing facilities are the United States, Israel, Mexico and the United Kingdom. Visit Perrigo on the Internet ( http://www.perrigo.com ).

Certain statements in this press release are forward-looking statements within the meaning of Section 21E of the Securities Exchange Act of 1934, as amended, and are subject to the safe harbor created thereby. These statements relate to future events or the Company’s future financial performance and involve known and unknown risks, uncertainties and other factors that may cause the actual results, levels of activity, performance or achievements of the Company or its industry to be materially different from those expressed or implied by any forward-looking statements. In some cases, forward-looking statements can be identified by terminology such as "may," "will," "could," "would," "should," "expect," "plan," "anticipate," "intend," "believe," "estimate," "predict," "potential" or other comparable terminology. The Company has based these forward-looking statements on its current expectations, assumptions, estimates and projections. While the Company believes these expectations, assumptions, estimates and projections are reasonable, such forward-looking statements are only predictions and involve known and unknown risks and uncertainties, many of which are beyond the Company’s control. These and other important factors, including those discussed under "Risk Factors" in the Company’s Form 10-K for the year ended June 30, 2007, as well as the Company’s subsequent filings with the Securities and Exchange Commission, may cause actual results, performance or achievements to differ materially from those expressed or implied by these forward-looking statements. The forward-looking statements in this press release are made only as of the date hereof, and unless otherwise required by applicable securities laws, the Company disclaims any intention or obligation to update or revise any forward-looking statements, whether as a result of new information, future events or otherwise.

Perrigo Company
http://www.perrigo.com

At present, animal tests are the only way of determining whether a particular chemical can cause an allergic reaction. Researchers working on the Sens-it-iv project are developing alternative methods that can reliably predict the allergy risk of chemicals without animal testing.

There is danger lurking everywhere in textiles, cosmetics, medicines, detergents, foodstuffs, toys, and even at work. Potentially allergenic substances surround us all the time. The dramatic increase in allergy-related diseases makes it increasingly important to take preventive action. Two years ago, the EU issued a new directive requiring all chemicals to be reassessed with respect to toxic risk. One very important question is "Which substances can lead to sensitization and from there to the development of allergies?"

In the past, tests had to be performed on animals in order to answer such questions. Scientists at the Fraunhofer Institute for Toxicology and Experimental Medicine ITEM in Hannover are currently engaged in work for the EU Sens-it-iv project to develop alternative methods that will one day eliminate the need for animal testing. "We have focused our attention on substances that are absorbed by the body via the lungs, i.e. by inhalation," says project manager Dr. Armin Braun. "We do not administer chemical substances to live animals to test for allergy risk; instead we use specimens of lung tissue." This tissue is generally obtained from rodents, and cut into very fine slices using a special, highly precise method. The chemical being tested is applied to these so-called precision-cut lung slices (PCLS) and the scientists then use various methods to evaluate the tissue’s reaction. This includes identifying which genes might be expressed in the tissue, or determining which protein molecules are produced in greater abundance by the cells. Are any of them implicated in the immune response process, i.e. are they likely to trigger an allergic reaction? By examining the tissue under a microscope, it is possible to observe potential interactions between the cells and the immune system. Because the PCLS method is based on whole sections of tissue, the researchers can observe physiological processes in natural cell aggregates, almost exactly as they would occur during an immune response in the body.

At present, the scientists are using chemical substances already known to provoke an allergic reaction, as a means of refining the PCLS method. But they soon intend to start testing many other substances that have not been evaluated before. These in-vitro tests performed in a culture vessel require far fewer animals merely enough to harvest the lung tissue. The main beneficiaries of Sens-it-iv will be industry cosmetics, textiles, pharmaceuticals and public authorities in charge of monitoring occupational health and safety.

FRAUNHOFER-GESELLSCHAFT
Hansastraße 27C
80686 Muenchen
http://www.fraunhofer.de