Posted by: Indonesian Children | April 6, 2010

ALLERGEN SPECIFIC IMMUNOTHERAPY

 ALLERGEN SPECIFIC IMMUNOTHERAPY

An update on subcutaneous immunotherapy, other routes of immunotherapy administration, different allergens and impact of immunotherapy on the natural history of disease.

  • Many double-blind, placebo-controlled studies confirm the efficacy of subcutaneous immunotherapy for treatment of allergic rhinitis, allergic asthma, and Hymenoptera venom hypersensitivity.
  • Studies are lacking that support immunotherapy with fungal extracts, other than for Alternaria and Cladosporium, and with cockroach extracts.
  • Although limited in number, some controlled studies have demonstrated efficacy of subcutaneous immunotherapy with multiple allergen mixes. However, there have also been negative studies.
  • There seem to be 2 distinct and perhaps sequential immunologic responses to immunotherapy, generation of regulatory T-cells (T regs) secreting interleukin (IL)-10 and transforming growth factor (TGF)-β and immune deviation from TH2 to TH1 responses.
  • Subcutaneous immunotherapy has reduced the development of new sensitizations in monosensitized patients and, in a few studies, has reduced the development of asthma in children who only have allergic rhinitis.
  • The beneficial effects of subcutaneous immunotherapy persist for years after discontinuation.
  • The use of subcutaneous immunotherapy is limited by the occurrence of local and systemic reactions (SRs) and the prolonged period required for build-up to maintenance dosing.

 

Historical Development

Subcutaneous administration of increasing doses of a grass-pollen extract to treat allergic rhinitis was introduced by Leonard Noon in 1911,1 with completion of his studies by John Freeman.2 Timothy grass was administered preseasonally or seasonally. This treatment was subsequently extended to other seasonal and perennial allergens and to the treatment of allergic asthma and rhinitis.3 Perennial administration largely replaced preseasonal treatment. While immunotherapy was initially used based on the clinical impression of efficacy, in the 1960s, definitive double-blind studies using ragweed pollen extract established that this was an effective form of treatment.4,5

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Clinical Efficacy

Many double-blind, placebo-controlled studies confirm the efficacy of subcutaneous injection allergen specific immunotherapy (SCIT) for treatment of both allergic rhinitis6 and allergic asthma.7 These studies showed efficacy with extracts of various pollens, animal danders, HDMs, and fungi. For most classes of allergens, results support efficacy. However, although a few small size studies report positive results treating patients with Cladosporium8 and Alternaria,9 studies supporting immunotherapy with many of the other available fungal allergen extracts are lacking.10

Most controlled studies included in SCIT meta-analyses that show clinical efficacy of SCIT for allergic rhinitis and asthma include only a single allergen extract. Although there are controlled studies that demonstrate efficacy for multiple allergen mixes for treatment of both allergic rhinitis4 and allergic asthma,11 the studies are more than 40 years old and there are no recent studies.

Mechanisms of Action

Along with evidence of the efficacy has come an understanding of the probable mechanisms by which SCIT alters the disease processes. The earliest objective evidence of an immune response was the observation by Noon that immunotherapy reduced conjunctival sensitivity to timothy grass extract.1 Subsequent observations confirm a reduction of sensitivity to the injected allergen in the skin, or topical allergen on the conjunctivae, nasal mucosa and lungs.12,13 Humoral responses were also observed, with first an increase and later a decline in specific immunoglobin(Ig)E14 and the generation of a blocking IgG antibody.15 However, studies failed to correlate these responses with clinical improvement.16

Research today is focused on changes in T-lymphocyte responses and 2 distinct patterns of change, which may occur sequentially. An event that occurs within 7 days at high allergen doses17 and 2–4 weeks at low allergen doses18,19 is the generation of regulatory T-cells secreting IL-10 and TGF-β19 accompanied by suppression of allergen-induced late cutaneous responses.17,18 This is followed at 6–12 weeks after initiating therapy by corresponding elevations in allergen-specific IgG4 and IgA that parallel a more delayed suppression of allergen-induced early cutaneous responses.18,19 A second and probably later immunologic response is immune deviation with a shift in the allergen specific T-cell response from predominantly TH2 to TH1.20

Impact on Natural History

Considering the profound effect on the immune response to the administered allergen, it is not surprising that SCIT alters the natural course of allergic diseases. Several studies have demonstrated that SCIT, when administered to monosensitized patients, reduces the likelihood of developing new sensitivities.21–23 Furthermore, the reduction in new sensitivities persists for at least 3 years after discontinuation of treatment.22,23 A similar inhibitory effect occurs for the progression to asthma in children suffering from only allergic rhinitis.24 Timothy or birch pollen SCIT reduced the development of new onset asthma during the course of 3 years of treatment25 and reduced the incidence of asthma with little loss of effect more than 7 years of posttreatment observation. The beneficial effects of SCIT on allergy symptoms persist for years after its discontinuation. In a prospective, placebo-controlled trial, subjects who discontinued timothy grass SCIT after 3 to 4 years of treatment had the same level of symptoms during the next 3 grass pollen seasons as did the group who continued on monthly maintenance injections.26

Alternative Approaches to Immunotherapy

Despite its clinical and disease-modifying efficacy, SCIT has some disadvantages: it is not ‘patient friendly’ because of the regular injections, which may arouse fear among children and some adults, and it has some indirect costs such as travel to the doctor’s office and lost work/school hours. The use of SCIT is also limited by the prolonged time for build-up required to reach maintenance levels of treatment and by adverse reactions. Attempts to improve the former have lead to trials with accelerated treatment schedules, while the latter has been addressed by modifying the allergen extracts or administering them by routes other than injection. Alternatives to the weekly build-up include administering clusters of 2 or 3 injections, usually 30 minutes apart, during a single clinic visit with visits spread over several weeks.27 This cluster schedule is not associated with an increased incidence of adverse reactions.28 However, a more rapid build-up, in which maintenance is achieved in just one or a few days, is associated with an increased incidence of reactions even when treatment subjects are premedicated.29 Extract modification includes adsorption of the extract to aluminum to achieve a depot effect30 and modifying the extracts with formaldehyde31 or glutaraldehyde32 to reduce reactivity with specific IgE. Recombinant technology is currently being used to produce altered proteins33 or peptides34,35 that retain T-cell epitopes but are no longer recognized by the specific IgE. Another approach is to combine the allergen with products, most extensively with monophosphoryl lipid A36 or CpG motifs,37 that stimulate the innate immune system thereby favoring a TH1 response.

Another approach is to administer the extracts by an alternative route, for example, orally38 or sublingually39 slowing absorption and presenting the extract to a different component of the immune system. Other alternative approaches are to administer the extract directly on to the respiratory mucosa, either into the upper or lower respiratory tracts.40,41 This approach can induce allergic respiratory symptoms, therefore, either modified extracts with decreased allergenicity are used42 or cromolyn sodium is applied to the mucosa before the allergen is administered to block the allergic reaction.43

REFERENCES, CHAPTER 2
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