Food Allergy - Immunotherapy

When your immune system freaks out and starts attacking the food you eat, something is terribly wrong. Somehow, your immune system has been tricked into making some really bad decisions on what’s good and what’s bad for you. Your immune system is simply out of whack.

One approach to bringing the immune system back in balance is to retrain it, through immunotherapy, so it no longer identifies harmless foods as enemy invaders. Immunotherapy attempts to correct your immune system’s poor judgment (in some cases) and strengthen it to fight disease (in other cases).

In other words, immunotherapy is any treatment that works to activate or deactivate the immune system:

  • Activate the immune system: When the immune system lets down its guard, you become more susceptible to disease. Immunotherapy can kick your immune system in the pants, so it does a better job protecting you. For example, cancer treatments (sometimes referred to as cancer vaccines) are now available for stimulating the immune system to fight specific cancer cells.
  • Deactivate the immune system: An over-reactive immune system can literally kill you when it’s acting like some out-of-control overachiever. In allergy, immunotherapy has traditionally referred to treatments that involve intentionally exposing people to what they’re allergic to — essentially desensitizing them to specific allergens over time. Medical professionals refer to this as “the development of immune tolerance” — making the immune system more tolerant of allergens.

Taking a little hair of the dog that bit you may seem, at first, to be some quack homeopathic treatment for allergies, but medical doctors have successfully employed such treatments for almost a century.

Allergy tests reveal what you’re allergic to: pollens, molds, or other allergens. Once your allergist identifies the allergens that ail you, she can prepare and administer allergy shots designed to make your immune system less sensitive to those allergens.

Allergy shots have been available for years but are primarily used to treat environmental allergies, such as hay fever. Do they work on food allergies? I get to that question later in the section “Treating food allergies with allergy shots.” You or someone you know probably has had allergy shots to treat everything from hay fever to asthma.

Following is a rundown of how a doctor typically determines which shots you need and administers the shots:

  1. Your doctor performs a series of allergy tests on you to determine what you’re allergic to.
  1. Your doctor prepares the shots based on your allergy test results. In other words, not all allergy patients receive the same shots.
  1. After a build-up period that normally takes 6 to 12 months, your doctor keeps you on a maintenance dose for the next 3 to 5 years.

Overall more than 80 percent of people with environmental allergies experience improvement with allergy shots. Allergy shots also have proven very effective for people with allergies to bees and other stinging insects. Allergy shots rarely work for eczema and often worsen the condition.

The major downside of allergy shots is that they can cause allergic reactions, sometimes even dangerous anaphylaxis. This should not be surprising since you’re actually being injected with the stuff you’re allergic to. In addition to the risk of severe reactions, allergy shots often result in significant inconvenience:

  • You have to get your shots at your doctor’s office.
  • You have to wait around for 20 to 30 minutes after each and every shot to make sure you have no reaction.
  • The doctor’s office must be equipped to deal with severe allergic reactions.

Some people cannot receive shots because their reactions are so severe, but most allergy patients tolerate the shots just fine. When you see such the high success rate for allergy shots in treating environmental allergies (an 80 percent success rate), you may be tempted to jump to the conclusion that drug companies would be able to develop similar vaccines for food allergy.

Unfortunately, up to this point, the effectiveness of food allergy shots has proven less promising. I describe the most promising new immunotherapy approaches, realizing that the medical community still has a lot to learn and that other methods may well be underway by the time you read these words. What’s most promising is that food allergy research is accelerating at a very rapid pace.

Sublingual Treatments

The membranes in your mouth can sometimes absorb trace amounts of a substance without hitting you with a full dose. Researchers surmised that perhaps by placing a small amount of an allergen under the tongue, the patient could absorb just enough of it to help desensitize the immune system without a significant risk of serious reaction.

In some cases, this ten-year-oldor- so theory has played out in practice through sublingual treatments. Sublingual treatment consists of placing a tiny amount of allergen extract — in the form of allergen drops — under the tongue, where the patient typically holds it there for a minute or two and then either spits it out or swallows it.

Researchers have performed over 200 studies to explore the effectiveness of sublingual immunotherapy on environmental allergies, such as allergies to pollens and dust mites, with very encouraging results. The great advantage of sublingual immunotherapy has been its safety record.

Although an itchy mouth is common, systemic reactions (reactions that travel to other areas of the body) are so rare that patients can take these allergy drops safely at home. The allergy community has shown great interest in applying this form of immunotherapy to food allergy. The following sidebar describes one study performed on hazelnut allergy.

Oral Immunotherapy

Oral immunotherapy is similar to the sublingual method — you take gradually increasing doses of an allergen to desensitize your immune system to it. Two key differences, however, set oral immunotherapy apart from the sublingual variety. With oral immunotherapy:

  • You actually eat the allergen rather than tucking it under your tongue.
  • You eat the food (or at least some concentrated form of the food protein) rather than an extract of the food.

The basic procedure for administering oral and sublingual immunotherapy is basically the same, except that in the case of oral immunotherapy, you actually consume the allergenic substance. Here’s how a typical oral immunotherapy treatment is done:

  1. Your doctor starts you on a miniscule amount of the food you’re allergic to.
  1. Over a period of weeks or months, your doctor gradually increases the dose.
  1. Assuming you can tolerate the dose you consume at the clinic, you take that same dose daily at home for a period of days or weeks.
  1. Assuming your symptoms don’t recur at home over that time, you go back to the clinic for your next dose increase.
  1. Once you’ve achieved the desired dose plateau, your doctor places you on a dose that you continue to consume daily at home for a period of months to years. Hopefully, you eventually achieve complete and long-term tolerance.

A few preliminary studies on oral immunotherapy have provided very encouraging results for milk, egg, and peanut allergy. We are currently conducting oral immunotherapy studies for both milk and egg allergy with high hopes that this method will prove to be both safe and effective.

So, where do you go for oral immunotherapy? Unfortunately, neither oral nor sublingual immunotherapy is likely to be approved for routine use in your allergist’s office for at least five years. But I believe that someday one or both forms of treatment will be approved.

We need at least 5 years though to work out the details, including how quickly to ramp up doses, how much of a food to recommend as a maintenance dose, how long to continue treatment before attempting a full-fledged food challenge, how to minimize the risks, and so on.

Protein Vaccines

While allergy shots and sublingual and oral immunotherapy expose you to the complete proteins that cause your immune system to overreact, modified protein vaccines expose you only to pieces of the proteins to reduce the risks of severe reactions.

A similar theory drives the development of other vaccines; for example, many anti-bacterial vaccines contain weakened or dead bacteria that can trigger your immune system to develop the required antibodies for fighting the disease without exposing you to the live, virulent bacteria.

Allergens are proteins comprised of long chains of amino acids. What your immune system recognizes in a protein are small segments called epitopes rather than the entire protein. The epitopes, which bind to IgE (and therefore may be responsible for severe allergic reactions) are different from the epitopes that your T cells recognize.

One food allergy treatment that uses a modified protein vaccine is called peptide immunotherapy, which uses small protein fragments (peptides) that bind to T cells. If appropriately designed, these peptide fragments would be unable to bind to the IgE (binding would cause allergic reactions), but the peptide fragments would still be able to stimulate suppressor T cells to render helper T cells unresponsive to subsequent allergen exposure.

Researchers have studied peptide immunotherapy in people with cat allergy and discovered encouraging results. So far, however, researchers have tested peptide immunotherapy for food allergy only in animals. In one such study, two doses of a peanut peptide mixture were administered to peanut-sensitized mice prior to performing a peanut challenge, and the mixture effectively reduced the risk of anaphylactic reactions.

More extensive desensitization protocols are being investigated in mice, and the first human trials will hopefully begin in the next few years. Molecular biology and chemical engineering have made great strides in the last few years. Humans can now modify genes, clone sheep, and engineer smart drugs.

We can even modify proteins to create mutant food proteins unable to bind to IgE but quite capable of interacting with T cells. Understandably, some people may be a little hesitant to be injected with a dose of mutant proteins, but the research shows some promise.

Here’s how the genetic engineers managed to mutate peanut proteins to treat people with peanut allergy:

  • The three major peanut allergens — Ara h1, Ara h2, and Ara h3 — were isolated and purified.
  • IgE-binding and T-cell epitopes were mapped, and the DNA encoding these proteins was isolated, sequenced, and cloned.
  • Engineered proteins were then created that differed by a single amino acid within each of IgE-binding epitopes. To IgE, this single amino acid tweak makes these engineered proteins like the surface of a non-stick pan, so very few of the proteins bind with the IgE antibody, but the proteins stick to T cells like Velcro, so they’re still able to promote the immune system’s suppressor T-cell responses, just like a bona-fide peanut proteins.

These engineered proteins have been tested on mice to determine their effectiveness in preventing peanut anaphylaxis. Researchers sensitize the mice to whole peanut and then desensitize them using the engineered proteins. Delivery by injection and both intranasal and rectal applications have now been studied with dramatic results, taking mice with severe peanut allergy and literally making the allergy go away.

In fact, the rectal delivery appeared most effective in mice, and these proteins are now being produced in a suppository form to be tested in people, hopefully starting in 2007 or 2008. Designing protein molecules that minimize IgE binding while preserving their ability to stimulate suppressor T-cells, should result in the availability of a well tolerated and effective food allergy treatment.

While most of these pioneering studies focus on peanut allergy, we could apply the same techniques to other foods once the technology has been perfected. On the other hand, if treatments with intact proteins in sublingual or oral forms prove to be equally effective, then we may not need to invest the time, effort, and cost to create these bio-engineered proteins. Only time will tell.

Homologous is a fancy word for “similar.” Researchers have known for a long time that peanuts and soybeans are similar — they share family ties, because they’re both members of the legume family. This kinship is also reflected at the molecular level — their respective proteins share significant characteristics.

These molecular similarities led some clever researchers to wonder if they could create an immunotherapy treatment for peanut allergy out of soybean. After all, soybean proteins can be viewed as natural mutants of peanut allergens and therefore may function as effective desensitizing agents in allergen specific immunotherapy.

To test this innovative theory, researches did what researches usually do: They rounded up some mice — in this case, mice that had peanut allergy. They then administered soybean immunotherapy to some of the mice, peanut immunotherapy to others, and a placebo to the third unfortunate group. What did they discover? Eureka!

  • The placebo group still had the peanut allergy, which is no surprise.
  • The mice that received peanut immunotherapy (using peanut rather than soy protein) experienced less severe reactions. Again, this is no surprise.
  • The mice that received soybean immunotherapy were as equally well protected as the mice that received peanut immunotherapy, and their clinical symptoms were significantly reduced compared with the placebo-treated mice.

If soybean immunotherapy can be used in patients allergic to peanuts and is effective, the treatment would provide an immediate and better tolerated therapeutic option for patients with peanut hypersensitivity. In addition, the same strategy may be useful for treating other food allergies; for example, chicken proteins may be effective in treating someone with egg allergy.

DNA Vaccines

Another novel approach to the treatment of food allergy currently under investigation is called DNA immunization. DNA is the genetic material that makes everything in nature unique. DNA immunization triggers the body to produce the very proteins that it’s allergic to, leaving most people sarcastically responding, “Yeah, that’ll work.”

The idea behind DNA immunization is that when the body produces the allergen from within, the immune system no longer views the allergen as a foreign invader, and hence has no reason to attack it. Here’s how it works:

  1. Bio-engineers build DNA that codes for a specific allergenic protein, such as peanut.
  2. This DNA is injected into the allergy sufferer — at this point a mouse, because we’re not sure yet how risky it is for humans.
  3. The immune system receives the DNA, and the body begins producing the allergenic protein.

This strategy has prevented the development of peanut allergy in mice, and some evidence suggests that it may be able to muffle existing peanut allergy in mice, as well. For food allergy, however, this therapy is far from ready for human experimentation, but similar strategies are being used to treat other diseases in people, including cystic fibrosis and sickle cell disease, so this may not be as far fetched as it sounds.

Ancient Chinese Herbal Remedy

If you read through earlier, you may think that I wouldn’t even give the time of day to someone claiming that an ancient Chinese herbal remedy can cure food allergy. Actually, I’m pretty open minded until research fails to uphold the claims of snake-oil salesmen.

In the case of a particular Chinese herbal remedy, research has upheld the claims of Chinese medical practitioners. Herbal remedies have been used in Asia for centuries for the treatment of allergic diseases as well as for a huge number of other conditions.

Several recent studies have tested whether these formulas — the most recent of which is called FAHF-2 (a combination of nine Chinese herbs) — are effective in treating peanut allergy in mice and to determine whether protection persists after therapy is discontinued.

The following items summarize the results of various tests using FAHF-2:

  • After challenges, all placebo-treated mice developed severe anaphylactic symptoms.
  • In five separate experiments, no sign of any allergic reaction was observed in FAHF-2-treated mice.
  • IgE levels were significantly reduced in FAHF-2-treated mice and remained significantly lower as long as five weeks after therapy.

How do FAHF-2 and other herbal remedies do their thing? At this point, we think that these herbal formulas contain some potent immunosuppressive properties. The actual mechanism of how they work is still being studied. Herbal therapies are now close to human trials.

Needless to say, both doctors and patients are showing a lot of interest in the results. Herbal preparations for allergies are now undergoing detailed analysis required by the FDA to ensure they do not contain any dangerous ingredients, but so far the safety profile looks reassuring.

How well will this work in people? How much would an allergy sufferer need to take and for how long? These are all open questions at this point, but as we move closer to finding out the results of these studies, we have a lot of room for enthusiasm.

Anti-IgE Antibody Therapy

The problem with most approaches to allergen immunotherapy is that they’re allergen-specific — they treat only one allergen, making treatment complex and expensive for the many patients with multiple allergies. Wouldn’t a single therapy, one that would be effective for multiple inhalant allergies as well as food allergies, be grand? Well, researchers are working on it.

One such therapy, already in clinical trials, involves the use of anti-IgE antibodies — bio-engineered IgG antibodies that bind freely to IgE, rendering it powerless. Once the anti-IgE antibodies bind with IgE, IgE is unable to bind to mast cells and basophils, so the massive release of histamine never happens.

Several clinical trials involving patients with allergic rhinitis and allergic asthma have been completed and one form of this treatment (omalizumab, sold as Xolair) has now been approved since 2003 for treating allergic asthma in adolescents and adults.

Results of studies on anti-IgE antibodies for food allergies show that the treatment is promising but not yet completely effective, as described in the following sidebar. Would Xolair (the drug that’s already available for asthma) work for food allergies? We don’t quite know yet.

Studies of Xolair for peanut allergy are in the works but will not be completed for several years, so no anti-IgE product will be approved for use for food allergy until these studies are completed. Although theoretically Xolair and other anti-IgE therapies hold out some hope, they have a few things working against them:

  • Anti-IgE is not a vaccine or cure, merely a means of suppressing reactions.
  • Anti-IgE needs to be given by injection at regular intervals — every two to four weeks — to be effective, and once it’s stopped, the protection quickly disappears.
  • Injections would be very expensive — about $1,000 dollars per dose with no guarantee insurance will cover them.
  • If the total IgE level (all IgE to all allergens circulating in your bloodstream) is too high, anti-IgE therapy is ineffective. For asthma, Xolair is not approved for use if the total IgE level is over 800. Unfortunately, many patients, including most patients with eczema and multiple food allergies, have levels far higher than that.
  • Possible side effects require further investigation. Anti-IgE therapy has not been studied in young children or in those with more severe forms of peanut allergy.

I feel strongly that anti-IgE therapy should be studied further and that it may be of great value to some patients. In the long run, however, one or more of the other forms of therapy described in this article are likely to have a greater ability to truly treat food allergy and do so without a lifetime of ongoing treatment.

Other Futuristic Allergies Treatments

Immunotherapy, especially the bio-engineered varieties, is hi-tech stuff, but other promising treatments are also being considered. In this section, I describe some of the hopeful treatments currently in research and development that you can expect to start hearing more about in the future.

Another take on the DNA immunization technique under investigation is immunization with DNA that’s conjugated (linked) to small strings of amino acids, forming what researchers fondly refer to as immunostimulatory sequences (ISS). These ISS contain repeated sequences of two specific amino acids called cytosine and guanine.

In animal models, ISS stimulate the immune system toward fighting infection while reducing its tendency to develop allergy. In addition, they clearly have the ability to turn down, and possibly even turn off, existing allergies.

No studies on the effectiveness of ISS therapy on food allergy in people have been done, but results from studies of ragweed allergy look very promising. Studies with ISS conjugation to peanut and other allergens are likely to begin in the next few years. Bacteria have a bad reputation.

Commercials and news headlines constantly disparage them for the role that a few black sheep in the bacteria community play in causing infection. You rarely hear about the many good bacteria working to make the world a better place. But good bacteria do exist, and they offer some hope in preventing the onset of allergies.

In scientific circles, these beneficial bacteria are often referred to as probiotics — live bacteria or their components that are reported to have beneficial effects on health by improving the balance of bacteria in the intestine. The major sources of probiotics are dairy products, including yogurt, that contain Lactobacillus and Bifidobacterium species.

Although the concept of probiotic foods was introduced more than a century ago, only recently have researchers evaluated probiotics in controlled clinical trials in the treatment of food allergy. Most current interest in probiotics focuses on their potential to prevent food allergy rather than turning off existing food allergy.

Even their effectiveness as a preventive is yet to be proven, but the theory makes sense and deserves further study. The likelihood that these products can actually turn off the immune system once the allergy has developed is small, especially compared to some of the truly exciting therapies discussed here.