Frew.qxp 7/8/09 4:07 pm Page 47
Allergen-specific Immunotherapy in Grass-pollen-induced Allergic Rhinoconjunctivitis
shown by skin tests, than comparable control groups. In terms of available on the use of SLIT in children, but it may be less effective
mechanism, it seems unlikely that SIT with house dust mites could in children than in adults.
directly affect B cells that recognise cat or grass pollen epitopes.
However, by treating the dust mite allergy, SIT may reduce nasal SLIT is used routinely in some parts of Europe (especially Italy and
inflammation and thereby reduce the likelihood of exposure to other France, and increasingly in Germany), but the doses and regimes
allergens proceeding to sensitisation. that are being prescribed are often different from those used in the
clinical trials. Overall, SLIT is likely to widen the scope of SIT and
To date, there is no evidence to support claims that SIT is different allow additional patients to receive specific therapy for their grass
from drug therapy in terms of influencing the evolution of pollen allergy. As with all forms of immunotherapy, patient selection
established asthma. To an extent, this reflects the reluctance is the key to ensuring that therapy is targeted to those who are
of physicians to use SIT to treat severe asthma. Studies that have likely to benefit from it.
investigated withdrawal of SIT have found rapid recurrence of
asthma symptoms, although rhinitis symptoms seem to show much Future Directions
more sustained relief. Further improvements in SIT should be possible. Conventional
SIT vaccines could be improved through using recombinant
Safety allergens, which would allow much better standardisation, as
The main factor preventing the wider adoption of standard SIT is well as opening the possibility of individualised vaccines for
the risk of serious adverse reactions. Generally speaking, SIT is safe patients with unusual patterns of reactivity. Initial studies have
in patients who do not have asthma, but significant numbers of shown that recombinant materials can achieve desensitisation, but
deaths have been reported in the UK and the US among patients they have not yet demonstrated superior efficacy compared with
with unstable asthma treated by SIT.
11
Different series have reported standard SIT vaccines.
14
systemic reaction rates of 5–35% in patients receiving SIT for
asthma. This compares with a rate of serious systemic reactions in Regulatory and licensing frameworks may present some difficulty
patients with rhinoconjunctivitis of about one in 500 injections. for this approach as, under the current rules, each individual
Systemic reactions are much more likely if the patient has an component has to be tested separately for efficacy and safety, as
intercurrent viral illness. Therefore, doses should be delayed if the well as any mixtures. It may be possible to get around this by
patient is unwell or has any signs of active asthma. preparing ingredients to be used in a personalised therapy rather
than off-the-shelf cocktails. Complex and carefully designed clinical
Patients with autoimmune disorders or malignant disease are not trials would be needed initially in order to validate the concept that
usually allowed to receive SIT. There is no hard evidence that SIT is personalisation leads to improved efficacy.
actually harmful, but it seems unwise to give immunomodulatory
therapy to such patients, not least because spontaneous and Another alternative approach with standard extracts is to inject the
unrelated variations in the autoimmune disorder or cancer might allergens directly into lymph nodes under ultrasound guidance.
be blamed on SIT. Other contraindications to SIT include significant Since less than 1% of injected allergen reaches the lymphatic
cardiac disease and treatment with beta-blockers. The issue here is system after subcutaneous injection, it should be possible to
not an increased risk of adverse reactions, but the fact that their achieve the same clinical effect by giving about 1% of the standard
physiological response to anaphylaxis will be impaired and in the SIT dose. Initial trials have shown comparable immunological and
event of a systemic reaction they may not respond to adrenaline. clinical efficacy with just three intranodal injections,
15
and further
follow-up data are eagerly awaited.
Alternative Forms of Immunotherapy
Conventional SIT is effective, but it is not perfect. Most patients Since the epitopes recognised by IgE molecules are t3D and T-cell
achieve only partial remission and the course of treatment is long and epitopes are short, linear-peptide sequences, it is possible to
can be risky. Over the past 15 years there has been increasing interest modify allergens or create peptide fragments that modulate T cells
in performing immunotherapy by the sublingual route, in which without risking anaphylaxis. Cross-linking allergen proteins with
allergen extracts are placed under the tongue. Evidence has now aldehydes reduces their allergenicity while preserving their T-cell
accumulated that sublingual immunotherapy (SLIT) is effective, with reactivity. Such allergoids have been shown to be effective in
reductions of 30–40% in symptom scores and rescue medication rhinoconjunctivitis due to grass pollen.
16
This approach can also
usage in patients with seasonal allergic rhinoconjunctivitis.
12
be combined with new adjuvants, for example monophosphoryl
lipid A (MPL) derived from salmonella endotoxin, which activates
Some treatment regimes involve a build-up phase, but others start Toll-like receptor 4 and promotes a Th1-pattern response to the
immediately with the full maintenance dose. Several large trials injected allergen.
17
have been conducted with a grass pollen tablet, which showed a
level of efficacy similar to that achievable with injection SIT. After In a placebo-controlled trial of over 1,000 patients with grass
the first year of SLIT, 82% of patients reported that their hay fever pollen hay fever, those who received four pre-seasonal injections
was better or much better than in previous years. In addition, the of the grass pollen allergoid-MPL preparation gained clear-cut
grass pollen tablet now has a product licence and is gaining benefits in the first year of treatment, with a 26.9% improvement
acceptance gradually, although there are some concerns among in symptom/medication scores in those who provided full data
healthcare purchasers about the potential costs if it is widely sets. Further work is needed to show whether additional benefit
used.
13
Currently, it is used mainly as a second-line agent for those accrues in the second and third years of treatment and whether
who have failed on standard drug therapy. Only limited data are the benefit is sustained.
EUROPEAN RESPIRATORY DISEASE 47