Allergenic Pollen in Europe and in the Mediterranean Area

SIT for asthma

The majority of clinical trials of SIT for asthma have compared SIT either with historical controls or with a matched placebo-treated group. To date, the effectiveness of specific SIT in asthma has rarely been compared with conventional management (with avoidance measures and conventional inhaled or oral drugs). One recent study assessed SIT in asthmatic children receiving conventional drug therapy and found no additional benefit in patients who were already receiving optimal drug therapy [10]. There are some significant criticisms of this study and further work of this type is urgently needed. It is also important that trials include analysis of cost-benefit and cost-effectiveness since purchasers of health care are increasingly demanding this evidence before agreeing to fund therapies.

A proportion of patients with allergic rhinitis go on to develop asthma each year. It has been suggested that SIT may modify the natural history of asthma in children who are known to be atopic but have not yet developed asthma. This annual rate of progression has been estimated at 5% in college students [11] but this is perhaps surprisingly an area of considerable ignorance. A number of long term epidemiological studies are now in progress, under the auspices of the ISAAC programme and should soon shed light on the rate of progression at different ages and the extent of regional and international variation. Only limited data is available to support the proposition that SIT may alter the natural rate of progression. An early open study using uncharacterised mixed allergen extracts supported this view, but among other problems, this study failed to allow for the spontaneous improvement that often occurs in asthmatic patients [12]. New evidence is now emerging to indicate that SIT can modify the natural history of allergic disease through childhood and into adult life [13]. If this is confirmed, it will have a major bearing on the economic and clinical arguments surrounding SIT and asthma. There is as yet no evidence to support claims 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.

The main factor cited against the widespread adoption of SIT for asthma is the risk of serious adverse reactions. In the UK between 1957 and 1986 twenty-six fatal reactions due to SIT were reported to the Committee on Safety of Medicines [14]. In 17 of the fatal cases, the indication for SIT was documented; 16 of these 17 patients were receiving SIT to treat asthma. Similarly, in the AAAAI confidential inquiry into SIT-associated deaths, asthma appeared to be in virtually all the fatal cases [15]. In those where asthma was not cited as a contributory factor, documentation of asthma status was missing and certainly bronchospasm was a cardinal feature of the clinical course of the anaphylactic reactions. The incidence of systemic reactions in patients receiving SIT for asthma varies between series and has been reported to range from 5% to 35%. The central issue in using safety as an endpoint is to recognise that all treatments carry risks. Where differential risks exist between therapies, a more risky therapy can only be justified if that therapy offers substantial additional benefit over the safer therapy. The science of assessing risk-benefit ratios is still in its infancy and we have to recognise that even when faced with the same facts, different patients and agencies can come to widely varying risk assessments.

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 ultimately to better vaccine products.
Since the epitopes recognised by IgE molecules are usually three dimensional whereas the epitopes recognised by T cells are short linear peptide fragments of the antigen, it should be possible to use peptide fragments of allergens to modulate T cells without risking anaphylaxis. Two distinct approaches have been tested. Either large doses of natural sequence peptides are given, deceiving the T-cell into high dose tolerance [16], or else an altered peptide ligand can be given. Both approaches require consideration of the MHC type of the individual undergoing treatment. By sequential alteration of Der p peptides, it is possible to suppress proliferation of T-cell clones recognising native Der p peptides, as well as suppressing their expression of CD40 ligand and their production of IL-4, IL-5 and IFN-. These anergic T-cells do not provide help for B-cells to switching class to IgE, and importantly this anergy cannot be reversed by providing exogenous IL-4 [17].
From epidemiological and experimental studies, we know that vaccination with mycobacteria has anti-allergic properties. In Japan, early vaccination with BCG was associated with a substantial reduction in the risk of developing allergy [18] although similar associations were not evident in Sweden [19]. In the laboratory, it has been shown that administration of BCG before or during sensitisation to ovalbumin reduces the degree of airway eosinophilia that follows subsequent challenge with ovalbumin (Fig 6). This effect is not mediated through any direct effect on IgE production, or blood eosinophil numbers, but is mediated through IFN- and can be reversed by exogenous IL-5 [20].
Two new approaches using DNA vaccines are also undergoing serious consideration. The first of these is a general approach, using CpG oligodeoxynucleotides (ODN). This technology is essentially a refinement of vaccination adjuvant technology, since CpG ODN have been shown to be the principal activity from Complete Freund’s Adjuvant. Pre-administration of CpG ODN prevented both airways eosinophilia and bronchial hyperresponsiveness in a mouse model of asthma [21]. Moreover, these effects were sustained for at least six weeks after CpG ODN administration [22]. Experiments are also being conducted with CpG ODN coupled to ragweed allergen, which enhances immunogenicity in terms of eliciting a Th1-type response to the ragweed allergen, but reduces its allergenicity [23]. Anti-sense DNA vaccines could also be used to downregulate airway adenosine receptors. In animal models of asthma this leads to a reduction in allergen-induced airway responses [24]. A contrasting approach is to use allergen-specific naked 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 [25,26]. 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, the potential for generating a powerful Th1-type response to ubiquitous agents means that this approach will need careful evaluation in animal models before it can be pursued in man.
Another approach that has reached clinical trials is to use a monoclonal antibody directed against IgE. By raising antibodies against the portion of IgE which is recognised by the high affinity Fc receptor, it is possible to derive anti-IgE antibodies which bind free IgE molecules but do not cross link IgE bound to the mast cell or basophil surface. Treatment with humanised monoclonal anti-IgE antibodies is extremely effective in reducing the serum concentration of free IgE, although the IgE seems to remain in the circulation in the form of immune complexes. Treatment with anti-IgE reduces immediate and late-phase responses to inhaled allergen [27,28]. When given over a 12 week period to patients with steroid-dependent asthma it was possible to achieve substantial reductions in the dosage of oral and inhaled steroids [29]. Anti-IgE should also work in patients with milder asthma, who are generally more likely to be atopic. However, the costs and inconvenience of anti-IgE may preclude its use in patients with milder disease. On the other hand, anti-IgE has the advantage over SIT of being a general therapy, and may work in patients with multiple allergic sensitisation, who are more difficult to treat with conventional SIT. Further work is needed to define the groups of patients who will benefit most from this approach.
Conclusions

Despite a century of use, the precise mechanisms of action of SIT remain uncertain. SIT is established as a treatment for allergic rhinitis and for venom hypersensitivity, but is more controversial when used to treat allergic asthma. When used in appropriately selected patients, SIT is effective and acceptably safe, but care is needed to recognise and treat adverse reactions. Appropriate training of allergists and SIT clinic support staff is essential. Future directions in SIT include the development of better standardised vaccines, and the use of recombinant allergens, both of which should improve the safety profile of SIT. In parallel, the development of more general immunomodulatory therapies may allow a more general approach to be taken, which would be particularly advantageous for those patients with sensitisation to multiple allergens.

Table 1

Possible mechanisms of immunotherapy

• 
  Induction of IgG (blocking) antibodies
  
• 
  Reduction in specific IgE (long-term)
  
• 
  Reduced recruitment of effector cells
  
• 
  Altered T-cell cytokine balance (shift to Th1 from Th2)
  
• 
  T-cell anergy
  

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