By David N. Leff
Frequent fliers are the first to notice that, instead of the hot meals once served in flight, airlines are presenting passengers with packets of pretzels or peanuts.
This economy move packs a potentially serious side effect when it comes to peanuts (Arachis hypogaea). These ubiquitous ground nuts are causing a growing incidence of mild to fatal food allergies throughout the industrialized world.
An estimated 100 children per year, in the U.S. alone, die from ingesting peanuts, to which their immune systems react by triggering systemic anaphylactic shock. Christopher and Patti Papkee, concerned parents of a little girl with peanut allergy, last year founded an international family support group (available online at PeanutAllergy.Com) to protect children with known allergic susceptibility to peanuts and their processed products.
Papkee pointed out to BioWorld Today that the U.S. Dept. of Transportation has mandated a three-seat buffer zone surrounding such young airline passengers, but this regulation is not being optimally enforced, he said.
Lurking in the tasty, crunchy, nutty fabric of a shelled peanut is a highly antigenic protein, expressed by a gene named AraH2. To an arm of the immune system called Immunoglobulin E (IgE), that allergen acts like a red rag waved in front of a color-sensitive bull.
¿Most food allergens,¿ explained British geneticist William Cookson, ¿contain many proteins. By looking through a number of people who react against different proteins, it is possible to work out which things most often produce an allergic reaction. Those are called major allergens. So, AraH2 is a particular protein that is a major allergen in people who have become allergic to peanuts.¿
The immune systems of such people, Cookson went on, ¿produce IgE against that peanut antigen, which binds to their immune system¿s mast cells. Then, for reasons not understood, they not only get a local reaction; some get a systemic anaphylactic reaction as well. About 100 children a year die of peanut allergy in the U.S. Even though it¿s not all that common, it¿s fantastically distressing, because a kid¿s completely well, then has a bite of something they¿re susceptible to, and then they drop dead. It¿s horrifying.¿
Many more infants and youngsters suffer from chronic symptoms, whenever they¿re exposed to peanuts. These range from itchy hives to intestinal upsets, wheezing, feeling faint, swelling of the mouth and throat, labored breathing, and even heart failure.
Proof-Of-Concept Proved Positive
Cookson, who is at the John Radcliffe Hospital in Oxford, U.K., is author of a ¿News & Views¿ editorial in Nature Medicine for April 1999, headed ¿Gene therapy for peanut allergy.¿ It comments on a research paper in the same issue, titled ¿Oral gene delivery with chitosan-DNA nanoparticles generates immunologic protection in a murine model of peanut allergy.¿ Its senior author is biomedical engineer Kam Leong, a professor at the Johns Hopkins School of Medicine, in Baltimore.
Leong made the point that this demonstrator-model oral vaccine ¿is not a therapeutic model. What we have tested is a prophylactic model. We vaccinated animals first, then challenged them with the antigenic peanut protein. In a real clinical situation, of course, you would not have that kind of a luxury.
¿In most cases,¿ he said, ¿you find children who have allergic reactions to this protein, then you try to alter their immune responses. That¿s not what we were able to show here ¿ not yet. What we were able to show in the immunized mice was that we shifted the immune response away from IgE synthesis to helper T cells. And then, when we challenged the animals, we got a much lower hypersensitivity response.
¿So, that is the difference,¿ Leong said. ¿We have been trying to tell people that this probably will still be a long way from clinical trials, because we still need to test the therapeutic model. I just want to be cautious in the sense that this is early work showing a very interesting proof-of-concept, that an oral vaccine could work.¿
To make it work, he and his co-authors joined a recombinant AraH2 gene with a natural biocompatible polysaccharide, called chitosan, derived from the shells of crabs.
¿At low pH,¿ Leong explained, ¿ chitosan has a net positive electrical charge. The DNA polyanion gene has a net negative charge. The two complex to form nearly spherical nanoparticles, in the range of 150 to 300 nanometers in diameter, which are taken up by cells. That¿s how we delivered the gene into the nucleus of the cells lining the gastrointestinal tract, the small intestine. The exact cell types we are not sure of yet.
¿When this gene was given as naked DNA,¿ Leong recounted, ¿it didn¿t work, because the enzymes in the GI tract at low pH would put down the DNA, [and] degrade the gene, before it had a chance to be taken up by the cells. But these small nanoparticles, complexed with chitosan, partially protect the DNA from degradation in the stomach.
Peanut Vaccine Only For Openers
¿But I would like to make a point that, to us, the most significant finding of this study is that oral delivery of a DNA vaccine generated a potent immune response,¿ Leong said. ¿Because, beyond this peanut allergy thing, what we are doing in the lab is trying to test the same concept for cancer vaccines, HIV vaccines and so on. You could imagine that an oral formulation is the most attractive formulation, particularly for mass immunization, say, in Third World countries.
¿Even in this country, the incidence of peanut allergy is not that high,¿ he said. ¿But, when it does happen, it is of course very painful, very traumatic to families, and it does get a lot of [publicity]. As academic scientists, we try to obtain proof of concept. But our goal, our challenge, is really to move it to such a stage that it could be helpful to mankind.¿ The university has a patent pending on Leong¿s approach, and he is holding discussions with interested companies.