New Concepts in Immunotherapy of Allergic Diseases

Anthony Frew Department t of Respiratory Medicine, Brighton General Hospital, Brighton, UK

Introduction Specific immunotherapy (SIT) is the administration of allergen extracts to modify or abolish symptoms associated with atopic allergy. The process is specific, in that treatment is directed to those allergens identified by the patient and physician as being responsible for symptoms. Patient selection is key - patients with perennial symptoms are unlikely to benefit from treatment with seasonal allergens such as grass and tree pollens, even if they are sensitised to the pollen as judged by skin tests. The decision to start SIT therefore requires careful assessment of the patient's condition and the role of allergic triggers in driving symptoms. The basic principles of SIT were developed 100 years ago [1]. Typically, patients are started on a very low dose of allergen, given by subcutaneous injection. The dose is then increased in a series of weekly injections until a maintenance dose is achieved. The maintenance dose is then given at 4-6 weekly intervals for 3 to 5 years. In Europe we generally use single allergens or mixtures of closely related allergens, but in the USA, it is common for patients to be treated with complex mixtures, compiled on the basis of the range of sensitivity found on skin testing. For some patients, typically those with insect venom hypersensitivity, the build-up phase may be compressed - several doses may be given on each day, or the whole series of incremental injections may be given on a single day (known as semi-rush and rush protocols respectively). The main drawback to rush and semi-rush protocols is the increased risk of adverse reactions, but full protection can be attained in a few days as compared to the three months required in the conventional regime. This may be particularly useful for protection against venom anaphylaxis, but is less of an issue for seasonal rhinitis. Mechanisms Several mechanisms have been proposed to explain the beneficial effects of immunotherapy: it remains unclear which are important and which are epiphenomena. Allergen-specific IgE levels rise during the initial phase of SIT, but fall back to pre-treatment levels during maintenance [2]. They may then gradually decline, or plateau, but do not generally disappear. The immediate skin test response may reduce after SIT, reflecting this drop in IgE, but this effect is relatively small compared to the degree of clinical benefit, and is not a good indicator of efficacy. In contrast, the late-phase skin test response virtually disappears after successful SIT. Similar patterns are observed for late-phase nasal and airway responses [3]. Allergen-specific IgG antibodies are usually induced by SIT. Originally this was thought to mean that IgG antibodies might block intercept allergens and prevent them form binding to IgE. However, the rise in IgG occurs after the onset of clinical benefit, and the size of the IgG response is not closely related to the degree of efficacy. We now know that IgG4 antibodies are stimulated by allergen-specific production of the cytokine IL-10. Several strands of evidence suggest that SIT induces allergen-specific T-regulatory cells that produce IL-10 on stimulation [4]. This seems a logical explanation of the IgG response, and also goes some way to explain the reduction in T-cell and eosinophil recruitment in response to allergen challenge observed after SIT [5]. These findings suggest that SIT has a modulatory effect on allergen-specific T-cells, which would explain why the clinical and late-phase responses are attenuated without such a large effect on allergen-specific antibody levels. SIT for venom hypersensitivity Anaphylaxis to hymenoptera venom is relatively rare, but can be fatal. Venom-specific IgE antibodies can be found in 30-40% of adults for a few months following a sting, but these usually disappear in a few months. Some individuals show a sustained IgE response, and are at risk of anaphylaxis to subsequent stings. Overall the risk of anaphylaxis declines gradually over time, reaching background population levels after about 10 years. Desensitisation with venom extracts accelerates the rate at which this risk decreases and provides protection against both field and laboratory stings [6]. SIT for allergic rhinitis SIT is effective in allergic rhinitis [7] even in patients with more severe seasonal rhinitis that is resistant to conventional drug therapy [8]. Patient selection is crucial. The allergic basis of the rhinitis should be carefully assessed both on history and on skin tests or blood tests, and other causes should be excluded. The benefits of SIT for perennial rhinitis are less than for seasonal rhinitis. In part this reflects the difficulty in determining the extent to which allergy is responsible for perennial symptoms. Allergy to house dust mite is common and may be asymptomatic. Conversely, there are other causes of perennial nasal symptoms including vasomotor instability, infection, aspirin sensitivity etc. Nevertheless, clinical trials have shown a definite benefit in appropriately selected subjects [9]. There is clearer evidence of efficacy in rhinitis due to pet allergy, with improved tolerance of cat exposure after SIT, confirmed both on challenge tests and simulated natural exposure [10]. SIT for asthma The role of SIT for treating allergic asthma is more controversial. The risk of adverse reactions is substantially greater in asthmatics, and almost all the fatal reactions to SIT reported in the literature were in asthmatics. On the other hand, meta-analysis of the various clinical trials confirms that SIT is effective in asthma, reducing symptoms, bronchial hyperreactivity and specific response to inhaled allergen [11]. However, SIT remains controversial as a treatment for asthma because of the potential side-effects. Effects on natural history of allergic disease SIT may modify the natural history of asthma in children who are known to be atopic but have not yet developed asthma. Only limited data is available to support the proposition that SIT may alter the natural rate of progression. An early open study using mixed allergen extracts supported this view [12], and more recent evidence from a randomised controlled trial has confirmed this with a reduction in the proportion of children who develop asthma that is sustained up to ten years after starting therapy (i.e. seven years after stopping treatment) [13]. If this result is widely accepted, it may have a major bearing on the economic and clinical arguments surrounding SIT and asthma. There is as yet no evidence that SIT is different from drug therapy in terms of influencing the evolution of established asthma. Studies that have investigated withdrawal of therapy have found rapid recurrence of asthma symptoms although rhinitis symptoms seem to show much more sustained relief after SIT. Future directions Developments in molecular biology should lead to improvements in conventional SIT. Possible avenues include the use of recombinant allergens, which would allow much better standardisation of allergen vaccines, as well as some fine tuning of vaccines for patients with unusual patterns of reactivity. Most allergic patients react to the same components of an allergen extract, the so-called major allergens, which are defined as those allergens recognised by over 50% of sera from a pool of patients with clinically significant allergy to the material in question. However, not all patients recognise all major allergens and some patients only recognise allergens which are not recognised by the majority of allergic patient sera. This latter group may not respond to standard extracts, but might be better treated by a combination of allergens to which they are sensitive. Until the advent of molecular cloning, this has been impossible to achieve. The availability of recombinant allergens for SIT should thus lead to better characterisation of the range of sensitivities, and may allow component-resolved diagnosis and treatment to become a reality. Peptide vaccines can modulate T cells without risking anaphylaxis. Initial studies in cat-allergic patients showed some promise, but this field of work has gone quiet recently. Two new approaches using DNA vaccines are also undergoing serious consideration. The first of these uses CpG oligodeoxynucleotides (CpG-ODN) to act as an adjuvant and deviate the response to injected allergen. The most promising studies have used coupled the immunostimulatory CpG-ODN to ragweed [14], while CpG-ODN used in isolation has not shown much effect. It may also become possible to use allergen-specific DNA sequences as vaccines. This technology is still in its infancy, but preliminary data suggest that giving "naked" DNA leads to production of allergens from within the airways epithelial cells [15,16]. Due to the different handling pathways for endogenous and exogenous allergens, it seems that the endogenously produced allergen elicits a Th1-type response and if this can be reproduced in allergic humans, it is hoped that this may overcome the existing Th2 -pattern response and eliminate the allergy. However, further work is needed to assess the safety of this approach in animals before it could be used in man. The other alternative approach to SIT has been the development of the sublingual route of administration. Following initial scepticism, a convincing body of research has emerged, indicating that sublingual immunotherapy (SLIT) is effective in allergic rhinitis. While many of the individual studies are small, meta-analysis has supported the claims of efficacy [17]. New preparations are currently being developed and launched across Europe. Thus far, only limited comparisons have been made with conventional injection SIT. Most allergists consider that SLIT is probably less effective than injection SIT, but this may be offset by greater convenience and safety. A fair amount of further work is needed before we can say that SLIT can achieve all the longer-term benefits that have been shown for injection SIT, but the immediate benefits seem real and worthwhile. Conclusions Despite a century of use, we still do not know precisely how SIT works. SIT is a useful treatment but patients need to selected carefully. Future directions in SIT include the development of better standardised vaccines, and recombinant allergens, as well as alternative routes such as sublingual administration, all of which should improve the safety profile of SIT. In parallel, we expect more general immunomodulatory therapies to be developed which may be particularly advantageous for patients sensitised to multiple allergens.