The research, published in the Nov. 12 online edition of the journal Allergy and completed jointly with scientists at UC-San Francisco, UC-Davis and UC-Berkeley, is the first to reverse pre-existing food allergies in an animal other than a mouse. The vaccines provide new hope to the millions of people who suffer from food allergies.
"Food allergy is an important problem for which there is no good treatment," said Dale Umetsu, MD, PhD, professor of pediatrics at Stanford and chief of the division of allergy and immunology at Lucile Packard Children's Hospital. "Developing a cure for this growing problem will help millions of people and save lives."
According to Anne Munoz-Furlong, founder and CEO of the Food Allergy and Anaphylaxis Network, a nonprofit patient advocacy group, "This study takes us one step closer to finding a treatment that will allow people to live without fear of having a reaction that could kill them."
Of the nine dogs in the study, four had peanut allergies and five had both milk and wheat allergies. Ten weeks after the dogs were vaccinated for the relevant allergenic foods, significantly greater amounts of the foods had to be used to generate a telltale allergic bump on the skin (called a wheal) in standard allergy skin tests.
In addition, all four of the peanut-allergic dogs tolerated eating much larger quantities of ground peanut after vaccination. As a group, they went from tolerating, on average, about one peanut to tolerating more than 37 peanuts. In fact, three of the four vaccinated dogs could eat a handful of peanuts - the maximum amount they were offered (about 57 peanuts) - without developing any symptoms. One of these dogs had a more than a hundred-fold increase in peanut tolerance - from half of one peanut to 57 peanuts.
Similarly, when milk-allergic dogs were fed 0.2 grams of milk two to four months after vaccination, they exhibited a 100 percent reduction in vomiting and a 60 percent reduction in diarrhea compared to their reactions prior to vaccination. The results for every test were statistically significant.
The dogs were cared for according to nationally accepted guidelines, and the tests performed were no different from those that are commonly used in human subjects. And, as in human research, dogs that had allergic reactions were immediately treated with antihistamines and recovered.
Food allergies occur in 1 to 2 percent of adults and up to 8 percent of children age 8 or younger. "Currently, the only treatment is to avoid the relevant food," said Umetsu. "Unfortunately, that's often difficult." Accidental exposures happen because peanut and milk products are present in many processed foods.
About 100 people, mostly children, die annually as a result of accidental exposures that produce a systemic allergic reaction called anaphylaxis, according to the National Institute of Allergy and Infectious Diseases. At its most severe, anaphylactic shock involves cardiac arrest and/or airway swelling so severe that a person can suffocate if not immediately treated with epinephrine, a strong antihistamine. Peanuts are the most common culprit.
Peanut and tree nut allergies have been on the rise in recent years, and the NIAID estimates that about 3 million Americans are affected annually. According to one study, these allergies' prevalence in children doubled from 1997 to 2002. The so-called "hygiene hypothesis" attributes this escalation to too much cleanliness in modern life. Under this theory, infections are critical to help protect people from allergies.
Umetsu's vaccines were designed with the hygiene hypothesis in mind. The vaccines' essential ingredient is a dead bacterium - heat-killed Listeria monocytogenes or HKL - mixed with peanuts, milk or wheat.
Umetsu began working with Listeria, a common food-borne bacterium that causes gastrointestinal infections, about 10 years ago. Perhaps, he reasoned, the incidence of Listeria infections has become less widespread than it once was because of greater attention to hygiene. "We thought that if we mimicked infection using HKL, we might engage the immune system in ways it was designed for, and in this way protect against allergy," he said.
The idea worked: Asthmatic mice did not develop wheezing when vaccinated with HKL mixed with an allergen such as a protein derived from eggs. "Bacteria and bacterial products can indeed induce protective responses," Umetsu said. He and his colleagues have also been studying how HKL affects the immune system. Results from those studies were recently published in Nature Immunology.
In a paper published in 2003, other researchers prevented peanut allergy in mice by vaccinating them with HKL and peanuts. Umetsu's research takes that approach to a larger mammal - an important step because dogs' allergic symptoms resemble those seen in humans, and dogs are close to humans on the mammalian family tree. Also, the Food and Drug Administration requires that studies be done in animals other than mice before a drug can be tested in humans.
Umetsu cautions that the vaccine is not yet ready for human testing. "We still have to do additional studies to see if the vaccine causes unforeseen problems in animals," he said. But he has great hopes for an effective food allergy treatment. His lab at Stanford is currently recruiting volunteers for a study of another peanut allergy treatment that works by a different mechanism: It rids the body of the antibody involved in allergic reactions.
"Over the next five to 10 years as we understand the causes of allergies better, we will have better recommendations and therapies that will in fact cure allergic disease," Umetsu said.
The research was funded by grants from the Lucile Packard Foundation for Children's Health, the National Institutes of Health and a gift from Howard and Susan Sosin. Umetsu's collaborators include O.L. Frick at UCSF, S.S. Teuber at UC-Davis and B.B. Buchanan and S. Morigasaki at UC-Berkeley.
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