November 2012

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Sneezing up a Storm: The Future of Allergies

Whether it’s itchy eczema or wheezy hayfever, allergies are familiar to us all in at least some capacity. The term ‘allergy’ is used to describe an adverse reaction of the body’s immune system to a specific food or substance in the environment, a so-called allergen [1]. Allergens are usually not harmful and provoke no reaction in people who are not allergic [1]. Some common allergens include pollen, mould, house dust mites and pets, nuts, fruit and latex [1].

An allergy develops because the immune system reacts to the allergen as though it is a threat [1]. The first time that an allergen is encountered in a susceptible person, B cells (white blood cells) produce an antibody called Immunoglobulin E (IgE) against the allergen [2]. These bind to the surface of specific immune cells, basophils and mast cells, ready to launch a response if the allergen “threat” is ever encountered again [2]. Upon encountering the allergen again, the allergen binds to the IgE on the surface of these immune cells and this signals to begin an allergic response [2]. This eventually results in the release of chemicals such as histamine, and prostaglandins [2] which give rise to the typical irritating and inflammatory allergic reaction symptoms: these include sneezing, wheezing, a runny nose, swelling, vomiting and itching [1]. However, in rare cases a severe allergic reaction can occur, called anaphylaxis or anaphylactic shock, which can be fatal [1]. This can involve a reaction in the entire body usually happens within minutes after exposure to the allergen [1]. Whilst this dangerous response is rare, it has been noted that allergies do impact on the sufferer’s quality of life [3], affecting their sleep, concentration and thus academic performance [3].

The numbers of people displaying allergies increases every year, with almost 50% of those affected being children [1]. For example, scientific studies have shown that people with food or digestive allergies increased by 18% from 1997-2007 [4]. Moreover, prevalence rates of patients being admitted for food allergy induced anaphylaxis increased by 350% in Australia between 1994 and 2005 [4]. It is not only the numbers of allergy patients, but also the complexity and severity of allergic diseases that appear to be increasing [5]. Therefore, do we expect to see this trend continue into future decades?

Some evidence would suggest that it depends upon the specific allergy. In terms of asthma and hayfever, it has been suggested that numbers of patients may now have peaked in some environments [6]. However, the more recent increasing incidence of food allergy has led some to speculate that as a society we may be entering a second wave of an allergy epidemic [6]. Nonetheless, it is difficult to speculate if and how allergy incidence may increase in future decades, as the actual causes for the current increases that have been observed still remain relatively elusive [7]. In fact, it is likely that multiple causes and risk factors are involved [6], ranging from increased air pollution, diet, nutrition and UV radiation [8] to a decreased exposure to bacteria in the environment via the “Hygiene hypothesis” [9] and genetic predisposition [10].

But with an estimated 1 in 4 people currently suffering from allergies in the UK alone [1], which might in fact increase in the future, what novel biological strategies and therapeutics are in the pipeline to fight allergies? What might the future bring? At the moment, allergy avoidance remains a key strategy, where patients should try to avoid the trigger for their allergy [11]. However, this is not always practical, especially for ubiquitous allergens such as dust mites, and there is debate over whether this is actually helpful in the long-term progression of the allergy or in reducing symptoms [12].

With the recent advances in molecular biology and proteomics, we are now able to more easily manipulate and develop modified whole allergen proteins, or specific fragments of them, which can be used as a safe, effective vaccines for allergies [13]. The strategy behind these vaccines it that a patient is treated with increasing doses of the troublesome allergen so that eventually they are tolerant to it and no longer mount an allergic response when exposed [14]. Being able to generate small fragments of allergen peptide for vaccines means that they can be circulated in the patient’s system with less risk of actually mounting a potentially dangerous or irritating response during these treatments [13]. Work on defining these fragments for food allergens has been reported, for peanut and egg allergies for example, and reports from experiments on mouse models using this strategy have been encouraging thus far [13]. This may be a viable therapeutic strategy for treatment of allergies in the future, but we will have to wait until human clinical trials are undertaken before its true potential is known.

However, there are also novel therapies that are not based on exposure to any sort of allergen. These have been cited as being especially promising to treat food allergies, as they would allow the treatment of multiple allergies all in one go [13]. One such example of this type of therapy would be using helminth worms. This is based on studies that have shown that there is a link between infection with parasitic worms and a reduced incidence of allergies; for example, worm infections have been shown to suppress allergic symptoms in mouse studies [15]. Specifically, in a mouse model of peanut allergy infection with the Trichuris suis worm lead to greatly reduced anaphylactic symptoms and a decrease in the production of peanut specific IgE [16]. As a result, Phase I clinical trials are currently being organised where patients would be given 100-2,500 worm eggs every other week for 3 months to assess the potential and safety of this therapy [16].

Another strategy has been to try to destroy the activity of the IgE that mediates an allergic response, so called Anti-IgE therapy [13]. The idea would be that antibodies are administered to patients that will bind to the IgE, rendering it unable to launch an effective allergic response [13]. Initial results were promising, with greater tolerance to peanut proteins observed in peanut allergy patients after treatment [13]. One anti-IgE therapy, Omalizumab, has made it through to clinical trials in patients, but was shown not to have statistically significant results, although a general trend towards increased allergen tolerability in treated individuals was again observed [13]. In the future, it may be possible to combine anti-IgE therapy with other forms of immunotherapy to aid the desensitization of patients to allergens [13].

A final example of this type of therapy includes using Chinese herbal therapy [16]. Whilst this may not seem like a ‘novel’ treatment in itself, Chinese formulations such as the Food Allergy Herbal Formula-2 (FAHF-2) isolated from nine different herbs, have been shown to be efficacious in protecting against food allergy induced symptoms in mice [16]. Mouse models have shown that this formulation has an immunologic effect on white blood cells, as well as decreasing the numbers of cells, such as mast cells, which mediate the allergic response. You may say that this is all very well, but is decreasing your allergic response in this manner actually safe and does this translate into humans? Early clinical studies with volunteer patients confirmed that FAHF-2 was safe and well tolerated by patients, as well as able to reduce the activity of basophils, the allergic response immune cells [16]. Further Phase II clinical trials are now in progress [16].

Conclusions

Whilst allergy prevalence has seen increases in epidemic proportions in recent decades, the causes for these changes are not clear and it is likely that a complex combination of factors is responsible. Without being sure of risk factors, it is impossible to predict how the prevalence of allergies will change in future decades. What is clear is that there is a drive for developing novel allergy therapies to more effectively treat these conditions in the future, based on our now increasing understanding of the biology behind the allergic response. Whether it’s worms, Chinese herbal remedies or various forms of immunotherapy, future research may hold the key to beating allergies.

References

[1] NHS Choices, Allergies, available from http://www.nhs.uk/conditions/Allergies/Pages/Introduction.aspx [Accessed 15th October, 2012].

[2] Suen, J-L et al. (2012). Alkylphenols – potential modulators of the allergic response. The Kaohsiung Journal of Medical Sciences, 28 (7): S43-S48.

[3] Rotiroti, G and Scadding, GK (2012). Allergic rhinitis – an overview of a common disease. Paediatrics and Child Health, 22 (7): 287-292.

[4] Burks, AW et al. (2012). ICON: Food Allergy. Journal of Allergy and Clinical Immunology, 129 (4): 906-920.

[5] Pawankar, R et al. (2012). Allergic diseases and asthma: a major global health concern. Current Opinion in Allergy and Clinical Immunology, 12: 39-41.

[6] Nwaru, BI and Sheikh, A (2012). Risk factors for the development of egg allergy: progress to date and future directions. Allergy, 67: 1325-1326.

[7] Behrendt, H et al. (1997). Air Pollution and Allergy: Experimental Studies on Modulation of Allergen Release from Pollen by Air Pollutants. International Archives of Allergy and Immunology, 113: 69-74.

[8] Carlsten, C and Melen, E (2012). Air pollution, genetics, and allergy: an update. Current Opinion in Allergy and Clinical Immunology, 12 (5): 455-461.

[9] Umetsu, DT (2012). Early exposure to germs and the Hygiene Hypothesis. Cell Research, 22: 1210-1211.

[10] Bouzigon, E and Laprise, C (2012). Comprehensive integration of genetic and environmental determinants to increase knowledge of allergic diseases. Current Opinion in Allergy and Clinical Immunology, 12: 447-448.

[11] Lieberman, JA and Nowak-Wegrzyn, A (2011). Vaccines and Immunomodulatory Therapies for Food Allergy. Current Allergy and Asthma Reports, 12: 55-63.

[12] Tovey, ER and Marks, GB (2011). It’s time to rethink mite allergen avoidance. Journal of Allergy and Clinical Immunology, 128 (4): 723-727.

[13] Lieberman, JA and Wang, J (2012). Nonallergen-specific treatments for food allergy. Current Opinion in Allergy and Clinical Immunology, 12 (3): 293-301.

[14] Allergy treatments, BBC Health, available from http://www.bbc.co.uk/health/physical_health/conditions/in_depth/allergies/allergicmedical_treatments.shtml [Accessed 23rd October, 2012].

[15] Pritchard, DI et al. (2011). Parasitic worm therapy for allergy: Is this incongruous or avant-garde medicine? Clinical and Experimental Allergy,42: 505-512.

[16] Henson, M and Burks, AW (2012). The future of food allergy therapeutics. Seminars in Immunopathology,34: 703-714.

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