SSC2A D10 Word Version Homepage Can Immunotherapy Cure Allergies? Project Aims: • To demonstrate an understanding of the basic pathophysiology of allergy. • To demonstrate an understanding of the main mechanisms of tolerance and their application in allergenimmunotherapy. • To discuss the literature surrounding specific immunotherapy (SIT), peptide-based immunotherapy (PIT) and the main methods of delivery. • To review the current evidence for the treatment of a) allergic rhinitis and b) peanut allergy, including the barriers and risks in the treatment of these. This site was made by a group of University of Edinburgh medical students who studied this subject over 10 weeks as part of the SSC. This website has not been peer reviewed. We certify that this website is our own work and that we have authorisation to use all the content (e.g. figures / images) used in this website. We would like to thank Dr Mackenzie for her guidance throughout this project. Total Website Word count: 9,538 Word count minus Contributions Page, References Page, Critical Appraisal Appendix, Information Search Report, Word Version Appendix and other sections clearly marked as Appendices: 5,952 Introduction Allergy as a concept was first introduced in 1906 by the Viennese paediatrician Clemens von Pirquet after he noted that some of his patients were hypersensitive to normally innocuous entities such as dust, pollen or certain foods. This understanding was further enhanced in the 1960’s with the breakthrough discovery of the antibody IgE. Today, we have a developed knowledge of allergies and are researching more than ever. However, allergy is an ever-expanding problem in the Western world - prevalence in the UK is thought to have trebled in the past three decades alone and is currently estimated to affect around one third of the UK population in one form or another, including asthma, eczema, allergic rhinitis and food allergy. It is common for children with one allergic disease to develop further allergic disease during childhood - a theory known as the "allergic march". The popular “hygiene hypothesis” states that lack of early childhood exposure to infectious agents, parasites and symbiotic microorganisms has increased susceptibility to allergy by dampening the immune system’s natural development and evolution. Another theory is that lack of exposure to an allergen in the early years can increase the likelihood of developing such an allergy later in life. One study found that Israeli children who are exposed to peanuts early on - through the popular peanut snack, 'Bamba' - were 10 times less likely to develop a peanut allergy than those in the UK where early avoidance is recommended. As aforementioned, research is ongoing for allergy management and treatment - immunotherapy being at the forefront. With a vast range of administration routes currently being researched, the question of specific versus peptide immunotherapy and the mysteries of dosage and efficacy yet to be fully answered, immunotherapy is a promising potential treatment which will require more investigation for a fully evidenced treatment to emerge. Aims Pathophysiology of Allergy Allergies are type 1 hypersensitivity disorders that trigger immune responses to allergens that would normally be registered as harmless. This hereditary predisposition to harmless antigens resulting in inappropriate IgE production and the consequent immune response is called atopy. The first time an allergy-prone person encounters an allergen the exposure should only produce a mild reaction, but repeated exposures may lead to more serious reactions due to the mechanism of sensitisation. The initial antigen is presented to naïve T cells by antigen-presenting cells (APCs), causing them to develop into TH2 cells and undergo clonal expansion. This leads to the production of cytokines: specifically IL-4 which acts in a positive feedback loop to promote differentiation of naïve helper T cells to TH2 cells as well as triggering increased IgE production, firstly by class switching and then by clonal expansion of B cell populations. These IgE antibodies circulate in the blood and bind to specific FcεR receptors on mast cells and basophils, making them sensitised to the allergen. IgE has a short half-life of only 2-3 days when in the blood, but when bound to mast cells and basophils this extends to 3 months. This is what causes the predisposition within sensitised individuals, which can occur due to several factors. Genetic factors result in T cells producing the ‘wrong’ cytokines; IL-4 and IL-13 production is favoured to induce class switching in B cells to IgE production. Environmental factors involve the hygiene hypothesis where individuals are exposed to fewer microorganisms by being brought up in environments which are ‘too clean’, leading to class switching to IgE as less of the other isotopes are required. Immediate phase reaction (type 1 hypersensitivity) Allergen crosslinking of FcεR-bound IgE leads to degranulation and release of vasoactive amines (histamines, prostaglandin D and platelet-activating factor) causing an immunological reaction creating allergic symptoms. These include vasodilation, increased vascular permeability, mucus production and bronchoconstriction. In severe cases anaphylactic shock can ensue which is a system-wide reaction affecting skin as well as respiratory and cardiovascular systems, often resulting in death if not treated quickly. Localised allergic reactions such as asthma or eczema remain within certain regions of the body dependent on exposure of allergen. Late phase reaction (allergic inflammation) Following migration to sites of allergen-exposure by chemotactic factors, antigen-specific T cells are reactivated and clonally expand. Local IgE-facilitated antigen presentation by dendritic cells increases T cell activation. This results in allergic rhinitis and asthma characterised by increased mucus production and bronchial epithelial cell apoptosis. Atopic dermatitis also results in keratinocyte apoptosis. Mechanisms of tolerance Tolerance is the natural phenomenon which prevents our body's immune system from reacting to innocuous or selfsubstances. It plays a critical role in our everyday lives where life-threatening allergic reactions can be a potential consequence. Immunotherapy aims to diminish this immune response by initiating tolerance: training the body to recognise and ignore these allergens. Tolerance Clonal deletion: Several mechanisms of tolerance in the human body have been recognised. In the thymus, T cells are positively selected for their ability to recognise 'self' antigens, and are then negatively selected if this results in strong binding. This is termed clonal deletion. It is also during positive selection that T cells are further divided into CD8+ and CD4+ T cells, depending on whether they recognise MHC class I or II molecules respectively. Those which recognise neither undergo apoptosis, ensuring that T cells with high affinity and those with no affinity for MHC are eliminated before becoming immunocompetent. Anergy: This is a state where T and B cells are temporarily static and unable to be activated. Anergy can occur in T cells at their initial meeting with antigens, prior to dendritic cells being in attendance. Similarly, in B cells anergy can occur prior to the arrival of T cells to costimulate them. The cells require multiple signals before they can mount an immune response and this is crucial in eradicating self-reactive immune cells which have managed to mature and migrate to the peripheries. Regulation: In contrast to the previous mechanisms, regulation has only recently begun to be understood. In 1970, work by Gershon and Kondo first suggested the existence of T cells other than helper T cells with the ability to tone down the immune response: so called 'suppressor' T cells. Their proposition was met with controversy and largely brushed aside as established evidence already existed for populations of T cells secreting various cytokines which modulated the immune response, such as the IL-10-secreting Tr1 cells, and without much other evidence this was widely accepted as their main suppressive mechanism. It was not until the mid-1990s that studies utilising cell surface marker CD25+ led to the identification of CD4+CD25+ T cells. Demonstration by Sakaguchi and colleagues that removal of this cell population triggers autoimmune disease – and furthermore enhances immune response to non-self antigens – supported their specific role in tolerance. The resulting population were named regulatory T cells, or natural Treg cells (nTreg) due to their continuous natural production in the thymus. Breakthrough research in 2001 led to discovery of the Foxp3 gene, the mutation of which causes IPEX in humans (immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome), resulting in autoimmune disease and severe allergy. Further study in mice showed Foxp3 expression was primarily limited to the CD25+CD4+ T cell population and, in addition, retroviral transduction of Foxp3 to naive T cells resulted in their conversion to cells resembling Treg cells and with a similar suppressive function. This research suggested the exciting potential for induction of Treg population of cells to treat immune disease. Allergen Immunotherapy Allergen immunotherapy aims to utilise the mechanism of regulation and the powerful influence of T cell populations to alter the allergic disease process. Allergen-specific effector T cells skewed towards a regulatory phenotype appear to relate to successful outcomes of immunotherapy. The major Treg cells immunotherapy aims to induce are nTreg cells and IL-10-secreting Tr1 cells. A combination of actions by Treg cells are thought to contribute to the induction of tolerance; the suppression of TH2 cells leads to reduction in several of its actions, such as IgE production and mucus production by the epithelium. IL-10 and TGF-β directly and indirectly regulate B cells and effector cells. Meanwhile, B cell activity is modified with a class switch from IgE to another non-allergy promoting antibody isotype: IgG4. This antibody diminishes the immune response by competing with Fcε receptors on IgE for binding antigen, limiting IgEactivated mast cell and basophil degranulation. IL-10producing B cells and memory B cells have been shown to contribute to expression of IgG4, which is found to be elevated in those demonstrating maintained peripheral tolerance. Beekeepers demonstrate the phenomenon of natural tolerance; during particular seasons they are exposed to more bee venom, and yet demonstrate immunity other than local effects at the site of the sting. It is suggested that this is due to an increase in IgG4 levels. Outwith these seasons of increased exposure, however, IgG4 levels decrease, which could be explained by the irregular frequency of exposure preventing long-term tolerance from being achieved. A trial by Caubet et al in egg-allergic children showed a decreased IgE/IgG4 ratio in tolerant children compared to those who experienced reactions to baked egg; the increase in IgG4 levels was only detected after a steady, prolonged period of antigen exposure. Other clinical research supports the vital role of these 'blocking' antibodies: in patients whose immunotherapy was discontinued, IgE levels returned to previous parameters but clinical tolerance alongside increased IgG4 was maintained for up to two years. Previously, difficulties in demonstrating the link between blocking antibodies and increased immune tolerance to allergens was due to lack of correlation between antibody levels after tolerance has been achieved, as these are noted to decrease. This has led to the consideration of an altered activity and affinity of specific IgG subsets, rather than serum levels, that is ultimately responsible for the long-term effects of immunotherapy. Advances in immunological research have uncovered the role of vital cell types in the immune response. Mechanisms of clonal deletion and anergy are relatively well understood whilst, despite decades of research, the regulatory effect of T cells still requires in-depth research. The classification of Treg cells remains controversial as their suppressive activities are not exclusive and have been exerted by conventional TH cell subtypes in some experiments. It is hoped that with continued intensive research geared towards a fuller understanding of the induction of T cell regulation, the field of immunotherapy can further progress towards improving the design and success of the clinical treatment. Clinical aspects of immunotherapy Allergen-Specific Immunotherapy Allergen-specific immunotherapy (allergen-SIT) involves administration of allergen proteins to patients in increasing, tolerable doses to build up peripheral tolerance and modulate the immune response. It is currently regarded as the single curative approach to allergic disease. The induction of peripheral T cell tolerance and promotion of Treg cell formation are key mechanisms in SIT; this approach has shown success in the clinical treatment of allergic rhinitis (AR) and asthma with many studies conducted over the last 80 years establishing its effectiveness. A major difficulty with SIT is the frequency of local and systemic adverse events, particularly during the early stages where serum IgE levels modestly increase as seen in the graph above. These adverse reactions range from mild to lifethreatening anaphylaxis, rendering SIT an effective therapy fraught with risk. Though this has been overcome in some studies by using ultra-rush procedures, it remains problematic: whilst high doses of SIT are associated with a higher risk of these adverse events, low doses are found to be ineffective. It is therefore critical to calculate an optimal dosing plan to strike the correct balance between the two. An effective dosing plan must ensure several factors: the induction of therapeutic tolerance, achievement of long-term change in T cell populations and absence of serious adverse effects. When explored within the autoimmune encephalomyelitis model of multiple sclerosis in mice, treatment with subcutaneous self-peptide immunotherapy demonstrated the strong dose-dependent nature of tolerance induction using several markers (e.g. IL-10 levels and severity of disease). The study also indicated that high initial antigen doses induced adverse effects across almost all of the mice. Dose escalation was therefore found to be vital, with the ability to diminish adverse effects and lower or delay the level of inflammatory cytokines. Many studies also indicate that the frequency of dose administration is essential. In immunotherapy treatment of mouse models sensitised to a grass allergen, lower allergen doses administered daily were found to have greater efficacy than higher allergen doses administered less frequently – despite identical weekly cumulative doses – suggesting that daily doses are preferential. A number of recent studies have confirmed the long-term clinical effects of SIT years after cessation of treatment. In one study for preventative treatment of childhood asthma, participants were successfully treated for 3 years with pollenSIT and followed up 2 and 7 years after cessation of treatment, demonstrating persistence of the original immunotherapeutic benefits. However, more evidence is needed to establish how long particular therapies must be administered for to ensure long-term maintenance of tolerance. Peptide Immunotherapy Peptide immunotherapy (PIT) involves the use of short synthetic peptides which represent dominant T cell epitopes of the allergen. These have a reduced ability to crosslink IgE and activate mast cells and basophils (mostly due to lack of tertiary structure) whilst still inducing a response in CD4+ T cells.. This simply initiates a T cell-dependent late stage reaction, thus reducing the health risks to patients. PIT has shown some beneficial results in early stage trials for the treatment of both insect venom and cat allergies, although research in these areas is ongoing. In 2002, Larche et al trialled PIT for the treatment of cat allergy and found that patients receiving Fel-d 1 (major cat allergen) peptides reported a significant improvement in their tolerance to cats at second follow-up, with only mild adverse reactions during treatment. Bias is reduced due to the study's doubleblinded nature, therefore this was a promising result. Various trials have been undertaken since, including one in 2011 by Patel et al which investigated long-term tolerance. 89 patients were enrolled in a 1-year blinded follow-up to PIT which showed improvement in symptoms compared to placebo.The importance of dosing on efficacy was also highlighted as there were significant differences in long-term tolerance between patients who underwent different dosing regimens. However, due to the variability of these results more research would be required to prove efficacy. In contrast to SIT, there have been no severe or anaphylactic adverse reactions in participants treated with PIT, therefore this could be hugely beneficial for treatment of children . There has been some research into the characterisation of T cell epitopes for peanut allergen but no clinical trials have yet been undertaken. Methods of administration Currently the evidence base for SIT is extensive, thus varying methods of administration centre around this form of immunotherapy. Subcutaneous immunotherapy Subcutaneous immunotherapy (SCIT) generally involves weekly allergen injections during a build-up phase, followed by monthly maintenance injections for 3–5 years . SCIT is highly effective in seasonal AR. A narrative review of 43 DBPC trials confirmed efficacy (greater than 30% when compared to placebo in 75-80% of studies). In general, clinical efficacy is accompanied by a marked reduction in requirements for anti-allergic medication during the pollen season and a marked improvement in patients' quality of life. Additionally, a Cochrane meta-analysis of 62 randomised controlled trials performed between 1954-1998 demonstrated significant improvements in allergic asthma symptoms, reduction in rescue medication and improvements in both allergen-specific and non-specific bronchial hyperresponsiveness. Unfortunately SCIT is time-consuming and requires medical supervision for the administration and immediate period following injection due to risk of severe systemic allergic reactions. In one particular report, for instance, 16/17 fatalities were in SCIT patients with co-existing poorly controlled asthma. For this reason, severe forms of allergic disease are not treated subcutaneously, e.g. peanut allergy. Sublingual immunotherapy Sublingual immunotherapy (SLIT) involves placing an allergen extract under the tongue for a few minutes. It is more patientfriendly due to the lack of injections so can performed at home; it additionally results in less severe reactions than SCIT. A 2011 publication tracking individual prescriptions for SCIT and SLIT in a national German database found that persistency rates for SLIT (51%) were significantly higher after two years than those for SCIT (34%). However, SLIT is still timeconsuming and needs to be administered daily for several years. There are many papers arguing that SLIT may be less effective than SCIT. Chelladurai Y et al directly compared existing clinical trials to assess differences in efficacy and safety between SCIT and SLIT with regards to AR. Focusing purely on the relief of AR symptoms, the results found that in 5 out of 6 trials, SCIT relieved symptoms more effectively than SLIT. Having said that, the last trial reported no significant difference between the two methods but this still leaves some evidence to support SCIT’s superiority. However, this review recognises that more direct comparison trials would be required to strengthen the evidence base. A further 2014 indirect comparison of DBPC trials in Canada specifically examined the literature around use of SCIT, Oralair and Grazax (SLIT tablets) and established a cost benefit in Oralair-prescribing without sacrificing safety or efficacy, a finding which could prove instrumental if transferable to other countries. However, it should be noted that the manufacturers of Oralair funded the trial so bias may have arisen; further research would have to be undertaken by a third party to determine the reliability of these conclusions. Oral Immunotherapy Oral immunotherapy (OIT) involves orally administering food allergens (whole or cooked) to patients. Early stage trials have shown promising results for this method in the treatment of peanut, egg and cow’s milk allergies. OIT is currently the most promising treatment for peanut allergy as it stimulates greater immunologic changes in volunteers, specifically lower peanut-specific IgE and basophil activation levels and raised IgG4, as well as participants being able to tolerate greater doses post-immunotherapy. OIT has the benefit of being much more patient friendly than other types of immunotherapy: it does not require injections and is easier to administer. However, it is also reported to cause unpleasant side effects such as diarrhoea and vomiting in some patients. Other Administration Routes Nasal administration: Involves an inhaled powder/solution or coated strips placed within the nasal passages. Potential therapeutic benefits have been demonstrated in the treatment of dust mite-mediated allergic rhinitis. Intralymphatic administration: Allergens are injected directly into the inguinal lymph nodes. One trial demonstrated that 3 intralymphatic injections provided similar benefits to 3 years of standard SCIT for the treatment of AR and led to less severe allergic reactions. However, some trials published did not demonstrate efficacy versus placebo. Epicutaneous immunotherapy (EPIT): A new, non-invasive delivery route. A DBPC trial of 132 patients with grass polleninduced AR showed significant improvement compared to placebo. Phase II peanut EPIT trials are currently being undertaken so its safety, efficacy and potential for use is yet to be seen. Allergic Rhinitis Allergic rhinitis (AR) involves the interaction of an allergen with the nasal airways, evoking an allergic response. It is very common in western countries, currently affecting over 20% of people in the UK although recent evidence suggests that its prevalence is gradually increasing. Although AR carries little risk in terms of mortality to afflicted individuals, there remain significant disturbances to daily life as well as associated comorbidities which may be aggravated. In most cases there is sufficient temporary relief of symptoms by taking antihistamines, eye drops and/or intranasal corticosteroids, but in severe cases this may not be enough. AR has therefore been a frequent target for clinical research into immunotherapy in order to relieve its characteristic coldlike symptoms. As it stands, the two main routes of administration in the UK are sublingually as Grazax tablets and by subcutaneous vaccine. A clinical trial conducted in 2010 investigated the ability of Grazax to induce immunological changes in patients with AR. This was a multicentre randomised DBPC trial, and baseline characteristics were measured to ensure that the control and active groups had similar IgE and IgG4 levels. The raw results showed a significant increase in IgG4 levels of patients in the active group, but no substantial change in the placebo group, suggesting that the results were valid and Grazax does have a positive immunological effect on the body. However the study did not mention whether or not Grazax actually relieved the patients’ symptoms – an important factor in measuring the efficacy of the drug. Alternatively, some trials have been more focused on patient satisfaction and relief of symptoms rather than solely immunological effects. Bergman et al conducted a large multicentre trial testing the safety and efficacy of SLIT for house dust mite-induced AR, and demonstrated that a significant reduction in symptoms could be achieved and maintained for at least a year following a year of therapy. Patient diaries were used in which participants scored their symptoms daily to gauge trends and detect self-reported changes, which was ultimately an effective method for indicating the improvements in quality of life experienced from a subjective point of view. This trial also caused very few side effects as a result of the sublingual route of administration: every participant who had taken one or more dose of therapy was included in the results for safety, and of these 509 randomised participants no anaphylactic events were recorded at any point during the course of treatment, or in the subsequent treatment-free year. This was replicated by Mosbech H et al in a recent trial (study population 608 across 8 European countries) where similar results for both safety and efficacy of SLIT to combat dust mite-induced AR and asthma were demonstrated. Both of the aforementioned trials utilised large study populations, double blinding and randomisation procedures which reduced the risk of bias during the trials, although it should be noted that both were sponsored by the pharmaceutical company whose drug was being trialed and so results may have been biased in this way. These results were again reinforced by a trial utilising the intralymphatic delivery route (though on a much smaller scale) which nonetheless demonstrated a significant improvement noted by participants in quality of life upon receiving the active treatment, as well as no severe adverse events. This data demonstrates the positive influence that immunotherapy can have on the lives of those suffering from AR, without causing unnecessary detriments to health. A 2013 retrospective analysis conducted in Florida investigating the issue of cost found sufficient evidence of economic benefit in immunotherapy in these individuals. This concurred with previous research which has similarly shown a stark advantage in providing this therapy in children to prevent the allergic march from progressing, whilst further demonstrating that the benefit was paralleled when introduced in adulthood. This study may have encountered bias due to its retrospective nature so should not be treated as absolute, but it may be a useful comparison should this issue be investigated in the UK. Peanut allergy Peanut allergy is the most common food allergy in adults and children, estimated to affect 1 in 50 young infants with evidence to suggest its incidence is constantly rising. Although children often grow out of other food allergies such as cow’s milk allergy, only around 20% of childhood peanut allergies will resolve. Clinical symptoms of the allergic reaction include hives, vomiting and anaphylaxis, though the form and severity of symptoms ranges widely between individuals. Currently treatment is limited to the management of symptoms, meaning the only option for allergic individuals is to simply avoid peanuts. Accidental exposure can only be dealt with by prompt treatment using antihistamines for acute cases or adrenaline in more severe reactions. In fact, evidence suggests that early treatment with adrenaline is crucial to prevent death in severe anaphylaxis. Unfortunately, in a minority of cases the allergic reaction still leads to fatalities. The significant prevalence of peanut allergy, as well as its potential to induce life-threatening anaphylaxis, makes it a great priority for immunotherapy research. Currently there is much promising research into peanut desensitisation through the use of immunotherapy. Originally, the method of administration investigated was subcutaneous. The first of two SCIT trials was undertaken in 1992, but was quickly halted after the death of a young boy due to a mix-up of injections. The subsequent trial, undertaken in 1997, showed too high a rate of systemic reactions to be considered in clinical practice. Peanut-immunotherapy has only begun to produce truly convincing results following the success of several groundbreaking OIT trials carried out in 2009. Clark et al found increasing amounts of peanut flour administered to four male children over several months demonstrated induction of tolerance. A post-intervention challenge showed an increased dose threshold in all participants ranging from 49-478 times greater. This demonstrated the great potential of OIT for peanut allergy sufferers, and the success has warranted an increase in research efforts over the past 5 years. However, results continued to suggest that wider application of the therapy should be approached with caution. The varying range of tolerance levels emphasised how the individual allergy profiles of each patient will lead to different responses to therapy. By 2011, the scale of the studies conducted had increased significantly with safety and efficacy of peanut desensitisation measured in an attempt to standardise the treatment for clinical use. In a multicentre randomised controlled trial involving 28 children, 16/19 subjects undertaking OIT were able to complete the 5000mg peanut flour challenge, compared with median tolerance of 280mg in placebo groups. This confirmed the ability of OIT to induce tolerance, although the small sample size limited its application to a wider population without further study. It is also important to consider that 3/19 subjects were unable to complete the treatment due to adverse effects, suggesting perhaps that some allergy profiles are unsuited to the treatment. The immunological outcomes measured in the study were comparable to other similar OIT studies, with those who successfully achieve tolerance usually showing an increased peanut serum-specific IgG4, decreased peanut-specific IgE and an allergen-specific decrease in some allergy-associated cytokines. The latest notable peanut desensitisation trial by Anagnostou et al (2014) is the largest clinical trial for peanut desensitisation to date, with 99 children involved in a randomised controlled crossover phase II trial. After the first phase, 84% of the active group showed daily tolerance (800mg peanut protein ingestion) compared to 0% of the control group. In the second phase the control group was given OIT, and showed similar development of tolerance (91%). Secondary to developing tolerance improvements on quality of life were also recorded. However, the trial does not take into account long-term effects of tolerance after immunotherapy, the understanding of which is arguably crucial for implementation into clinical practice. It should be noted that the study population was limited to individuals aged 7-16, so extrapolation of data may be restricted as a result. Alternative administration routes have also been explored to establish if there is a safer method for the therapy. SLIT has shown some promise; in a 2013 randomised DBPC multicentre trial, 70% of participants were successfully desensitised to 496mg of peanut protein. The safety advantages of SLIT compared to OIT is reported by the World Allergy Organisation in their SLIT position paper. This is due to the typical dose of peanut protein used being approximately 1000-times less in SLIT in comparison to OIT. In the aforementioned 2014 OIT trial, at least 81% of participants experienced adverse effects (ranging from oral pruritis and nausea to laryngeal oedema), whereas in the 2013 SLIT trial only 37% experienced any side effects at all. Although peanut OIT has greater immunological effects, SLIT may have particular clinical value for those who are unable to tolerate OIT as it has fewer adverse events. Conclusion The Future of Immunotherapy Significant knowledge has been gained regarding the suppressive nature of the immune system and the roles of particular cell types over the past decade. Identifying antibodies and mediators has aided our understanding of the mechanism behind therapy and allows measurement of its clinical effect. However, some aspects of the regulatory system still require study, particularly concerning the delivery of therapy that can ensure long term changes and maintained tolerance, as this remains a barrier to the ultimate goal of immunotherapy in curing allergy. Immunotherapy is an exciting field, with emerging routes of administration currently under trial which aim to improve efficacy and ease of use whilst minimising side effects. Despite reducing treatment duration and increasing patient compliance, some show less effect than the traditional routes, or even no benefit against placebo. Research on dosing plans has also been conducted to maximise therapeutic benefits, but results are often specific to certain diseases and may not be transferable to other allergies. With more ongoing trials, new evidence will hopefully be developed for improving treatments. Allergic Rhinitis (AR) Many studies have demonstrated the clinical effects of immunotherapy to tackle AR; however, these benefits are usually relatively small (~20% reduction in symptoms or 1/3 of treated asthmatics being able to cease inhaled corticosteroid use after a year) and so do not have high enough impact on patient experience to warrant its frequent use. This, coupled with the cost of the treatment, may indicate a redundancy in this treatment at its currently proven efficacy. In 2004, data was compiled from numerous national sources to gain understanding of the burden of allergic disease. This research demonstrated that not only was the UK the country most affected by allergic symptoms in Europe, but that these effects correlated with significant financial impact upon the NHS. The majority of this financial burden was linked to prescription of treatment (representing over 10% of the GP prescribing budget), alongside GP consultations and hospital admissions. Despite being a generally non-life-threatening condition, the cost related to AR sufferers may still be considered in terms of working days lost due to symptoms plus any treatment requirements, especially if they progress onto other related conditions, such as asthma. Immunotherapy has been proven in one trial to reduce need for inhaled corticosteroids in asthma patients; a treatment which is both costly and has many associated risks. Early intervention may be hugely beneficial in preventing this 'allergic march', and therefore avoiding further expense for both the individual and the healthcare system. Immunotherapy for AR may be one of the closest to routine clinical use in the UK, with many other European countries already providing this disease-modifying treatment over symptom control. However current efficacy would need to be improved upon before routine clinical use would provide both sufficient improvement to patients' quality of life as well as financial benefits. Peanut Allergy The promising results from peanut desensitisation trials have warranted huge attention not only from the NHS but also from the media, and have sparked complex debates questioning whether or not this treatment is ready for clinical practice. Some reviews maintain that the risks of OIT are greater than those of peanut avoidance, and believe not enough is known about the topic of dosing regimens, patient selection or large scale administration. In addition, limited long term studies into the therapy means there is a significant lack of evidence to suggest sustained desensitisation is possible, and furthermore there are fears over other long-term effects which may put those who receive the treatment at long-term risk. A review of peanut immunotherapy by Anagnostou and Clark looked at several studies involving longer-term outcomes, and concluded that long-term tolerance to peanut does occur in a small proportion of those receiving OIT but larger studies will be required to fully tackle this question. On the other hand, it has been argued that the potential benefit of immunotherapy outweighs the risks associated with desensitisation due to the extent of the negative effect on quality of life that peanut allergies are shown to have. The same review also comments that there have been no significant long-term unexpected reactions, suggesting that the fears over long-term desensitisation are unjustified. This is of particular interest when taking into account the fact that over half of allergy-related deaths are due to peanut allergy. In the USA, a number of health centres currently offer desensitisation programs, carried out at medical allergy centres. In 1989, the Joint Task Force (JTF) on Practice Parameters was formed with the aim to provide a comprehensive evaluation of the current literature regarding food allergy management and treatment. The parameter currently recommends that OIT is not ready for clinical practice due to insufficient evidence regarding its therapeutic benefit over the risk of therapy, although it should be noted that current research is progressing quickly with the hope that this therapy will soon be available for routine use. A Final Word We thoroughly enjoyed this project as it allowed us to relate the science of allergy to our own lives and personal experiences. Having been exposed to positive media coverage of allergen-immunotherapy, we were curious as to why it is not routinely offered. However, this project has transformed our perception of the complexity of treatment development. Expanding our knowledge of the pathophysiology of allergy allowed us to understand the complex nature of allergic disease. Furthermore, by appraising the literature surrounding immunotherapy, we were able to discern the barriers to implementation in clinical practice. As future medical professionals we hope that with more definitive research these barriers will be overcome and implementation of immunotherapy into clinical practice will become a reality for all allergic disease.