Oral and Sublingual Immunotherapy as Treatment for Food Allergy and Anaphylaxis

An allergic response in the human body begins upon first exposure to the allergen.  (National Institute of Allergy and Infectious Diseases, 2013)  Upon the advent of the allergen, the immune system creates one type of antibodies, known as specific immunoglobulin E, with specific affinity to that substance.  (Lerner, 2010; National Institute of Allergy and Infectious Diseases, 2013.  For a diagram of an antibody, see image 1.)  A group of immunological molecules known as interleukins promote the cloning of these IgE antibodies.  (Robinson, 2013)  During the second exposure, there is a much larger immune response and elevated production flood the bloodstream with allergen-specific IgE molecules.  (Robinson, 2013)  These antibodies move throughout the bloodstream and attach to the antigen binding cites of specialized immune cells known as mast cells and basophils. (Urry, 2011; National Institute of Allergy and Infectious Diseases, 2013; Urry, 2011) IgE levels are typically very low in the bloodstream non-allergic person, but during an allergic reaction, the body begins producing excessive amounts of the allergen specific antibody.  (de Weck, 2012; Cohen, 2012)  The IgE molecules do not remain in the bloodstream for a long period of time.  (Cohen, 2012) Instead, immediately after its proliferation, the substance binds very strongly to the membrane of mast cells in bodily tissue and blood basophils, both of which are unique types of immune system inflammatory cells.  (Tsai, 2012; de Weck, 2012; National Institute of Allergy and Infectious Diseases, 2013)  As inflammatory cells, both mast cells and blood basophils contain “inflammatory mediators,” most commonly histamine and serotonin.  (de Weck, 2012)  The strong binding of IgE molecules to the high-affinity receptors of the inflammatory cells causes cross-linking between adjacent IgE molecules.  (Tsai, 2012; Cohen, 2012)  This cross-linking triggers a series of biochemical reactions and cascades within the mast cells that eventually result in the cell’s “degranulation.” (Tsai, 2012)  When the cell becomes “degranulated” its membrane bursts and massive amount of granule-associated mediators are released.  (Parker, 2007; Tsai, 2012)  These granule-associated mediators, or inflammatory mediators, are liable for the majority of signs and symptoms associated with allergic reactions.  (Tsai, 2012)  The most common granule-associated mediator in an allergic response is the molecule histamine, which induces inflammation in various tissues, although a variety of other molecules can be produced throughout the course of the reaction. (de Weck, 2012; Cohen, 2012)  Histamine induces dilation and increased permeability of small blood vessels in various body tissues and constriction of the bronchi.  (Robinson, 2013)  These symptoms result in fluid loss and swelling of the tissues.  (Robinson, 2013)  For diagrams of the cell response to IgE, see images 2-4.

Though the cause of food allergy is unknown, the disorder’s effects on the body are well documented and well understood.  (Staff, Mayo Clinic, 2011)  The mast cells, primary proliferators of an allergic reaction, are most common in the gastrointestinal tract, respiratory tract, and skin.  (Cohen, 2012)  Therefore, it is unsurprising that these areas are the most common sites of allergic reaction in the human body.  (Cohen, 2012)  Though allergic symptoms vary widely between individuals, a handful of them are common to most people who have food allergies.  These include, itching of the mouth, swelling of the lips and the tongue, symptoms that affect the gastrointestinal tract, including vomiting, diarrhea, abdominal cramps, and abdominal pain, hives, eczema and other skin issues, constricted throat or breathing, and a drop in blood pressure.  (National Institute of Allergy and Infectious Diseases, 2013)  The inflammatory mediators released by the affected cells bring on these archetypal symptoms.  (Tsai, 2012)  If the reaction is very severe, it can trigger a response known as anaphylaxis.  This response is marked by an incredibly wide range of symptoms, most notably, though, are swelling throughout the body tissues, wheezing, weak pulse, shock, and fainting.  (National Institute of Allergy and Infectious Diseases, 2013) Such reactions are frightening, unexpected, and have the potential to be deadly.  Children and adults who live with this condition have constant anxiety about anaphylaxis and other severe reactions from ingestion and contamination.  (Fleischer, 2013)  Allergies are the single most cause of days missed from school and work, and studies have shown that food allergy has significant effects on the social activities, meal preparation, and psychological state of children impacted by the condition.  (Flesicher, 2013; Bollinger, 2010; Lerner, 2010)  Though some children eventually grow out of their allergies as they age, many do not, especially those with peanut allergy.  (Cohen, 2012; Fleicher, 2013)

Currently, there are no cures for food related allergies.  (Fleischer, 2013)  For many other types of allergy, subcutaneous shots containing progressively higher amounts of the allergen have been shown to desensitize the patient and often reduce allergy symptoms.  (Fleischer, 2013)  However, when trials of subcutaneous injections were conducted on patients with peanut allergy, many individuals had adverse reactions, and the practice was deemed unsafe.  (Fleischer, 2013)  At the moment, patients with food allergies are advised to practice strict avoidance of the dangerous food.  (Cohen, 2012)  This can be very difficult, and there is a high likelihood of possible cross-contamination of foods in cafeterias and other public dining facilities.  If an individual’s food allergies are very mild, his or her symptoms can be treated with drugs known as antihistamines.  (Staff, Mayo Clinic, 2011)  These drugs negate the more mild effects of histamine and reduce the symptoms of the condition.  More severe allergic reactions and anaphylactic reactions are treated with epinephrine injections and trips to the emergency room.  (Staff, Mayo Clinic, 2011)  Epinephrine counteracts the symptoms of high levels of histamine, increasing blood vessel diameter, reduces blood vessel permeability, and relaxes the bronchi.  (Robinson, 2013)  Yet, these treatments are only temporary.  They treat the symptoms of allergies but they do not remedy the underlying intolerance that causes the reaction. 

For years, the means by which to remedy allergic intolerance has eluded scientific researchers.  There have been no broadly available therapeutic options for allergy suffers, and there have been myriad severe and fatal anaphylactic reactions brought on by contact with food.  (Fleischer, 2013) At long last, however, there is hope for those who suffer from these allergies, which comes in the form of oral and sublingual immunotherapy.  Oral and sublingual immunotherapies, first studied more than 100 years ago, have only recently come to the forefront of scientific research.  (Nowak-Wegrzyn, 2011)  During oral and sublingual immunotherapy, patients are administered small doses of the allergic food, either mixed into other non-allergic foods or under the tongue in extract form, respectively.  (Nowak-Wegrzyn, 2011)  The amount of allergens in these doses is gradually increased over the course of many weeks, resulting in an elevated tolerance to the substance in question. (Nowak-Wegrzyn, 2011) Patients beginning treatment first establish the amount of allergen they can consume without inducing a reaction.  (Fleischer, 2013)  After the initially dosage is established, each individual begins a series of daily build-up doses, each marginally greater than the last.  (Burks, 2012)  Patients periodically test their resistance to the allergen during “food challenges” wherein an individual consumes incremental amounts of the substance in order to determine his or her tolerance. (Fleischer, 2013)  The dosages can continue as long as the individual desires, or until an adverse reaction occurs.  (Burks, 2012)  The immunotherapy trains the body, through repeated expose, to tolerate what it had once rejected.  (Fessenden, 2012)

Though oral and sublingual immunotherapy procedures are still in trial phases, the results have been promising.  (Fleischer, 2013)  Sublingual immunotherapy treatment has been shown to raise tolerance in patients allergic to kiwi, hazelnut, peach, milk, and, most recently, peanut.  (Fleischer, 2013)  In individuals allergic to peanut, the most deadly known food allergy, sublingual immunotherapy raised tolerance from less than two grams of peanut protein to over ten grams in some cases.  (Fleischer, 2013)  Tolerance increased greatly when therapy was continued over many more weeks.  (Fleischer, 2013)  A similar study of oral immunotherapy conducted with egg protein was even more successful, with 70% of participants able to consume a cumulative dose of five grams of powder at ten months of treatment.  (Burks, 2012)  Oral and sublingual immunotherapy show great promise as food allergy treatment.  Measurements of the immune components of the subjects also revealed encouraging results.  In studies of the peanut specific antibody levels in immunotherapy patients, trial participants were found to have a decreased range of allergen-specific IgE molecules and greater levels of polyclonal allergen-specific IgG₄ serum.  (Vickery, 2012; Burks, 2013; Fessenden, 2012)  IgG₄ is another antibody, the serum of which is essential to the promotion of IgE in allergic reactions.  (Vickery, 2012)  There was also a decrease in peanut-specific interleukin production; interleukins, which promote the propagation of IgE molecules, are key to a strong allergic response.  (Blumchen, 2010; Robinson, 2013)  All of these biochemical signs correlate with a reduction or possible discontinuation of allergic response.  Furthermore, the treatment was found to be incredibly safe.  (Hofmann, 2009)  Very few individuals had adverse reactions, and those reactions were always in the hospital during build up days, where they could be safely treated.  (Hofmann, 2009) Unlike subcutaneous immunotherapy, which was discontinued because it was too dangerous for many patients, oral and sublingual immunotherapy treatments seem to be safe, even for those with serious peanut allergies.  (Blumchen, 2010; Hoffman, 2009)

Food allergy is a serious medical condition that affects approximately 20% of Americans today.  (Lerner, 2010)  For many years, individuals with the condition have lived in fear of anaphylactic shock and severe reaction.  (National Institute of Allergy and Infectious Diseases, 2013) A cure, other than symptomatic treatment, has long evaded researches and medical practitioners.  (Burks, 2012)  Recently, however, oral and sublingual immunotherapy have risen to prominence.  (Nowak-Wegryzn, 2011)  By slowly increasing consumption of allergen, these techniques increase body tolerance to the offending substance.  (Fleischer, 2013)  The treatment results in decreased diversity of allergen specific IgE and increased levels of allergen specific IgG₄, both of which are good indicators of decreased allergic response.  (Vickery, 2012)  The treatment was found to be both safe and very effective.  (Hoffman, 2013; Fleischer, 2013)  It seems that the future advancements for allergy suffers lie in the very substances to which they are allergic.  As oral and sublingual immunotherapy gain prevalence and become widely used, one day we may see a world without food allergy. 

Appendix

Image 1

Image from the Biology 570 Immunology PowerPoint

Image 2

This image gives a basic overview of the IgE propagation, binding, and subsequent histamine release in allergic tissue

Lewis, Ricki. An Allergic Reaction - Overview. McGraw-Hill Companies, Inc, Digital Image. Nutri-Living, nd. Web. 25 Feb. 2013. <http://dft.ba/-allergicreaction>.

Image 3

This image shows the specific IgE molecules on an immune effector cell, and their cross-linking in the presence of an allergen.

Nature Reviews. Allergen Activation and Cross-Linking of IgE molecules. Digital image. Nature. Nature Reviews, n.d. Web. 25 Feb. 2013. <http://www.nature.com/nrd/journal/v3/n7_supp/images/nrd1408-f1.jpg>.

Image 4

An image displaying the various paths of mast-cell activation.  Note the presence of IgE and allergens, as well as the granule-associated mediators leading to inflammation of the tissue.

Mast Cell Activation. Digital image. AccessScience. McGraw-Hill Education, 2012. Web. 25 Feb. 2013. <http://www.accessscience.com/content/Mast%20cells/900114>.

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