Vincent St Aubyn Crump – January 2004

The prevalence of allergic diseases such as asthma and allergic rhinitis has substantially increased over the past few decades, and despite the introduction of increasingly potent and effective anti-symptomatic drugs we have been unable to halt the increasing prevalence or find a cure for these diseases. There is therefore a definite need for new disease-modifying treatments that will prevent or reverse the chronic allergic inflammation.

Specific Allergen Immunotherapy

Immunotherapy — sometimes called allergy vaccine, desensitisation shots, or hyposensitization shots — is delivered through the use of injections containing small amounts of allergen/s given on a schedule over a period of time. The goal is to decrease the body's sensitivity to the allergen/s injected. Allergens are the allergy-causing substances to which the allergic individual reacts. The purpose of allergy (vaccine) shots is to increase tolerance to the specific allergen/s being injected.

To be effective and reduce adverse events, allergy shots are given on an incremental increasing dose schedule. Typically allergy shots are given once or twice a week for about three to six months. After that, they are given about once a month for three to five years. If there are no adverse reactions, the allergen dose is increased each time a shot is given. Gradually the body learns to accept the allergen as the harmless substance it is. As this happens, allergy symptoms should decrease.

The potential for severe side effects (including anaphylactic shock) associated with conventional allergen-specific immunotherapy limits its widespread use & novel strategies or alternative approaches to minimize side effects and improving efficacy are being considered.

Specific allergen immunotherapy was first used in 1900, when ragweed injections were proposed as therapy for hay fever. Advances in allergen immunotherapy have depended on the improved understanding of IgE-mediated immunologic mechanisms, the characterisation of specific allergens, and the standardisation of allergen extracts. Numerous well-designed, controlled studies prove that allergen immunotherapy is efficacious in treating allergic rhinitis, allergic asthma, and stinging insect hypersensitivity.

Role for anti-IgE in combination with specific allergen immunotherapy

The most advanced novel therapeutic approach that tries to interfere more specifically with immunological mechanism underlying allergies is anti-IgE therapy. Application of anti-IgE effectively reduces IgE serum levels regardless of allergen specificity. This treatment has been successfully tested in patients with asthma, allergic rhinitis, and food allergy. It shows significant efficacy in reducing symptoms and reducing medication use. This treatment is limited by high costs and the necessity for permanent treatment.

The strongest argument in favor of allergen-specific immunotherapy is the potential to cure allergic diseases, which has been demonstrated with allergic Rhinitis, insect venom allergy and to a lesser degree asthma. The wider use of immunotherapy is limited by the potential of life-threatening side effects. A combination of anti-IgE and allergen-specific immunotherapy was shown to be superior to each single treatment protocol in children and adolescents with allergic Rhinitis, as demonstrated by reduced symptoms and rescue medication use (1).

Oral immunotherapy (desensitisation) in food allergy

Current figures show that up to 5% of children and ~2% of adults suffers from food allergy. In the USA approximately 150 people die from food anaphylaxis each year. Currently avoidance is the only recommendation to provide to these patients. Recognition of the potential hazards of food hypersensitivity has prompted allergists to seek for effective treatments of this condition already decades ago.

Oral desensitization’s to foods, mostly to milk, have been reported in numerous limited series but with various results (2-4).

Recently Patriarca et al. published a series of 59 patients with food allergy who underwent an oral desensitization protocol (5). This was a mixed population of adults and children. 29 were allergic to milk, 18 to egg, 11 to fish and 9 to other foods.

The diagnosis relied on skin prick tests and / or serum specific IgE levels (RAST- type). Double-blind placebo control food challenge (DBPCFC) procedures were also used in some patients. Specific oral desensitization protocols for the different foods were then applied to all subjects. The author reported successful desensitization in 24 of 29 patients with milk allergy, 13 of 15 with egg allergy, and 8 of 11 with fish allergy. Unfortunately this study was not validated by a control group and was not blinded.

Immunotherapy with genetically engineered reagents

Allergen-specific immunotherapy is the only antigen-specific and hence causal form of allergy therapy. It has been recently demonstrated that allergen-specific immunotherapy can prevent the progression of allergic disease from mild (e.g. hay fever) to severe (i.e. asthma) manifestation of allergy (6).

Several factors (e.g. maturation of pollen, degradation of proteins) influence in an unpredictable manner the composition of the allergen extracts and hence allergen contents in different extracts can vary markedly. Furthermore contamination with allergens from other sources has been reported. Standardization of allergen extracts regarding all the important allergens is therefore an impossible task. Using recombinant allergen molecules it has now become possible to analyze the immunological effects of extract-based immunotherapy.

It has also been shown that extract-based immunotherapy can induce new IgE specificities against new allergens. One study with birch pollen-specific immunotherapy showed that 29% of the treated patients developed new IgE specificities to allergens that were not recognized before therapy. These data indicate that patients might benefit if they were treated according to their individual sensitization profiles with purified recombinant allergens.

The published data so far clearly demonstrate that genetic engineering represents a standardized procedure for the controlled reduction of allergen activity. It is believed that this technology will deliver safer, possibly more effective patient-tailored vaccines of high quality for the therapeutic and prophylactic vaccination against type 1 allergy.

Immunotherapy with mycobacteria

Several epidemiological studies provide support for the “hygiene hypothesis”, which suggest that a cleaner environment and fewer childhood infections cause the increase in allergic diseases.

The developing immune system apparently requires microbial exposure in early life to stimulate Th1 lymphocytes. The relative absence of microbes thereby favors the development of Th2-driven responses, which is associated with allergic diseases. Recent studies have shown that markers of poor hygiene such as hepatitis A, Helicobacter infection and infection with herpes simplex virus was associated with less asthma, hay fever and allergen sensitization. Similarly, exposure to Mycobacterium tuberculosis or to the environmental mycobacteria were proposed to protect from allergy, introducing the concept that the administration of mycobacteria and their products may therefore be used as vaccines aimed at reducing Th2 responses.

Evidence for mycobacteria protecting against allergic diseases

One study among 867 Japanese children all immunized with bacillus Calmette-Guerin (BCG), showed that responders to tuberculin had lower levels of IgE and Th2 cytokines, and a lower prevalence of atopy and allergic diseases when compared with the tuberculin non-responders. However, most subsequent studies failed to confirm this inverse response between tuberculin responses and allergic diseases. This include one Australian study testing the hypothesis that neonatal BCG vaccination is associated with reduced prevalence of allergic sensitization, asthma, eczema and hay fever during childhood. This study failed to demonstrate a significant change in the rate of allergic sensitization between vaccinated and non-vaccinated individuals.

Is Mycobacterium tuberculosis different from other subgenus of Mycobacteria in its immune response?

The answer is probably yes. The other strains common in mud and untreated water, unlike M. tuberculosis have been present throughout human evolution and have been shown to have a different immune response.

It is found that M. vaccae induces anti-inflammatory changes in the lung and is acting outside the Th1 – Th2 shift.

In accordance with the hygiene hypothesis it has been consistently found that autoimmune disease in susceptible strains of rats or mice develop earlier and at a higher rate among animals bred in a specific pathogen-free environment than among animals bred in a conventional environment. Furthermore, the frequency of atopic diseases is increased in patients with diabetes and rheumatoid arthritis, suggesting a common mechanism underlying infection-mediated protection against autoimmunity and allergy. Moreover some of these autoimmune diseases can also benefit from treatment with mycobacteria. For example diabetes is prevented in non-obese diabetic mice by infecting the young mice with mycobacteria.

Mycobacteria induces T regulatory cells

Recent data suggests that M. vaccae stimulates an anti-inflammatory network that inhibits both Th1 and Th2 cells and therefore explains the recent epidemiological reports that not only Th2- but also Th1-mediated diseases are on the increase.

Immunotherapy with mycobacteria

Clinical studies with M. vaccae treatment in adults with asthma and rhinitis or in children with atopic eczema demonstrated clinical benefits, as measured by a reduction in use of rescue medication, the severity of disease or inhibition of inflammatory markers.

In contrast, however, another study using lower dose of M. vaccae in asthmatic patients did not show any beneficial effects. All patients in that study was prescribed inhaled steroids, and it is possible that the regulator T cells, normally induced by M. Vaccae was Suppressed (inhibited) by the steroids.

Conclusion

It is reasonable to propose that a general deficiency of regulatory T cell activity might be responsible for the increase prevalence of asthma, and other allergic diseases. However, it remains to be proven whether it will be possible to use mycobacteria selectively to induce allergen-specific T regulatory cells, which will subsequently lead to the inhibition of allergic disorders in humans.

References

(1) Kuehr J, Brauburger J et al. Efficacy of combination treatment with anti-IgE plus specific immunotherapy in polysensitized children and adolescents with seasonal allergic trinities. J Allergy Clin Immunol 2002; 109:274-280

(2) Bauer A, Ekanayake MS, et al. Oral rush desensitization to milk. Allergy 1999; 54:894-895

(3) Patriarca G, Schivano D, et al. Food allergy in children: results of a standardized protocol for oral desensitization. Hepatogastroenterology 1998; 45:270-291

(4) Wuthrich B. Oral desensitization with cow's milk allergy. Pro! Monogr Allergy 1996; 32:236-240

(5) Patriarca G, Nucera E, et al. Oral desensitization treatment in food allergy: clinical and immunological results. Aliment Pharmacol Ther 2003; 17:459-465

(6) Moller C, Dreborg S et al. Pollen Immunotherapy reduces the development of asthma in children with seasonal rhino conjunctivitis (the PAT- study). J Allergy Clin Immunol 2002; 109:251-256

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