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World Allergy Organization
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Novel Treatment Strategies in IgE-Mediated Allergy

New Directions in Immunotherapy

Hans-Jørgen Malling
Allergy Clinic, National University Hospital
Copenhagen, Denmark

Allergy is a systemic inflammatory disease with varying degree of disease manifestations from different shock organs. The orientation of the in utero Th2 screwed immune response into the future allergen-specific dominated Th1 or Th2 result in either non-atopic individuals or clinical allergic diseases. The early allergic response is dependent on the IgE-mediated release of mast cell-derived mediators such as histamine and leukotrienes. The late allergic response is caused by the cellular inflammatory response caused by infiltration of the airway mucosa with activated eosinophils and CD4+ T-cells of the Th2-type expressing mRNA predominantly for IL-4 and IL-5.

In most allergic patients the only treatment option is exclusively pharmacotherapy, and supplementary allergen-specific immunotherapy is only offered to a few patients. This paradox is not related to a lack of clinical efficacy (1) but rather to most physicians selecting a treatment that reduces or eliminate the symptoms (drugs) without any impact on the pathophysiologic mechanisms involved in the allergic inflammation. Only occasionally physicians prescribe treatments with the capacity to interfere with the regulatory mechanisms of mediator release and the inflammatory response (immunologic treatments). The contradiction is, however, not that simple, as the pharmacological treatment is highly effective and is applicable without important limitations to the vast majority of patients. However, a growing interest has emerged looking at the possible advantages of a treatment strategy interfering more fundamentally with the basis mechanisms of the disease, and with the prospect of changing the natural outcome of the allergic sensitization (disease-modifying treatment).

The development of novel approaches of disease modifying immunotherapy in allergic diseases is dependent on advances in our understanding of the molecular mechanisms of the allergic inflammation. While many novel forms of immunotherapy have shown significant promise in animal models their safety and efficacy in human subjects is only starting to be evaluated.

Allergen-specific immunotherapy
Conventional subcutaneous injection immunotherapy
Subcutaneous immunotherapy represents the standard immunotherapy care of allergic patients (2). The clinical efficacy has been documented in most controlled studies, and the magnitude of efficacy is equivalent or even to better than pharmacologic treatment (1). Although the level of evidence for the long-term efficacy and the preventive capacity of subcutaneous immunotherapy is still incomplete, it has a capacity to prevent the development of new sensitizations in monosensitized patients (3), and to prevent the development of asthma in rhinitic patients (4). Of major concern is the risk of inducing systemic anaphylactic reactions. The mechanisms of the classical subcutaneous allergen-specific immunotherapy are complex. In inhalant allergy redirection of the allergen-specific Th2 response towards a Th1 switch (immune deviation) and production of IFN- has been shown (5).

In parallel with the elucidation of the immunologic regulation of the allergic inflammatory reaction, the importance of a comprehensive knowledge of allergen extracts has emerged. The problems of currently used natural allergens are the inborn capacity to induce anaphylaxis due to cross-linking of IgE and the subsequent release of allergic mediators. Allergens may be modified as allergoids, isoforms or by side-directed mutagenesis to have a reduced IgE-binding capacity while retaining the immunologic activity and consequently allow the administration of larger doses implying improvement in clinical efficacy without compromising the crucial safety aspects (6). Animal experiments suggest that the clinical efficacy may be reinforced by combining allergens with cytokines (IFN-, IL-12) (7).

Local immunotherapy
Due to the small but still potential risk of inducing anaphylaxis by injection immunotherapy, several attempts to alternative administration of more safe allergen-specific treatment have been investigated. As allergic inflammation is expressed predominantly on mucosal surfaces, local as opposed to systemic immunotherapy is an attractive therapeutic option. The most popular and promising are sublingual immunotherapy. The clinical efficacy of sublingual immunotherapy has been convincingly documented in controlled studies (8, 9). The major questions to be answered are the long-term efficacy (does the clinical effect persist after terminating treatment?) and the preventive capacity (prevention of new sensitizations and deteriorations of disease severity). Among the advantages are the safety profile allowing patients to be treated outside the doctors office that might imply dissemination of specific treatment to more patients. However, the precise role in the treatment strategy of sublingual immunotherapy still has to be defined.

Peptide-based immunotherapy
The rationale for peptide-based immunotherapy is to induce peripheral T cell tolerance (anergy) without cross linking IgE and thus avoid the problem of anaphylaxis potentially associated with traditional whole protein-based allergen immunotherapy (6). Animal studies have demonstrated that peptides derived from the major cat allergen Fel d I can induce T cell tolerance and that the failure of T lymphocytes to respond to subsequent allergen challenge may be due to an absence of T lymphocyte co-stimulation. Clinical studies showed that subcutaneous injection of two peptides derived from Fel d I resulted in a modest improvement in symptom scores in cat allergic subjects (10). Furthermore, a considerable frequency of systemic reactions to the injections of Fel d I peptides suggest that the potential for anaphylaxis to peptides is still significant (11). More recently, shorter Fel d 1 peptides (16 residues vs 27 residues in the earlier studies) have been investigated to determine whether these peptides will be clinically effective without side effects. Preliminary studies suggest that a single injection of 12 of the shorter Fel d I peptides can inhibit the cutaneous late-phase response to whole allergen, and that multiple peptide administrations could reduce the IgE-mast cell-dependent early response in cat allergic asthmatics (12). The mechanisms of action of peptide immunotherapy seem to be related to down-regulation of cells and cytokines through the induction of IL-10 (anergy or tolerance) (13).

Specific immunotherapy combined with anti-IgE
Injection of monoclonal anti-IgE antibody reduced IgE-mediated symptoms independently of the allergen specificity. A controlled study combining specific immunotherapy in birch and grass pollen rhinitic patients with anti-IgE or placebo showed an additional symptom/medication score reduction of anti-IgE of about 50% over specific immunotherapy alone when administered after the induction treatment (during seasons) (14). Side effects related to treatment were more common in the specific immunotherapy plus anti-IgE groups (25%) versus 16% in the immunotherapy plus placebo groups indicating that the addition of anti-IgE does nor eliminate side effects during maintenance treatment. Of considerably interest would have been to elucidate if anti-IgE could reduce immunotherapy-induced anaphylactic side effects during the induction phase.

DNA Vaccines
The potential of immunostimulatory DNA sequences containing a CpG motif to inhibit the Th2 immune response and associated airway reactivity has been demonstrated in animal models of asthma (15). The immunostimulatory DNA sequences (unmethylated CpG motifs) mediate this effect indirectly by activating the innate immune system to generate cytokines (IL-12, IFN-) which redirect the immune response from a Th2 to a Th1 response. Additional studies have utilized conjugation of the immunostimulatory DNA sequences to an allergen protein such as ragweed to target the immunostimulatory DNA sequence and the allergen protein to the same antigen presenting cell and enhance the Th1 immune response to the allergen. Preliminary studies in humans utilizing a ragweed protein (Amb a I) conjugated to immunostimulatory DNA have demonstrated that the conjugate is less allergenic than the ragweed protein alone based on basophil histamine release assays in vitro, and skin test reactivity in vivo (16). Ongoing clinical studies with immunostimulatory DNA and immunostimulatory DNA conjugated to protein allergens will determine the safety and efficacy of this immunomodulatory approach in subjects with allergic rhinitis and asthma.

Conclusion
In the discussion of the applicability of immunologic treatment of allergic diseases, several aspects have to be taken into consideration. Although the clinical efficacy of conventional anti-allergic drugs is high (under optimal conditions), the low compliance and the emotional unwillingness to use prophylactic drugs limit the usefulness in daily clinical practice. The prospects of interfering causally in the pathophysiologic mechanisms involved in the allergic inflammatory reactions and the potential for preventing new sensitizations and progression of disease severity are important elements to be considered in the debate of the optimal disease management. Allergen-specific approaches to therapy offer the best change of modifying the disease processes without impinging negatively on the rest of the immune system. The optimal anti-allergic treatment implies a therapy that is safe, inexpensive, easy to administer, effective and preferable with a capacity to interfere fundamentally with the immunologic regulation of the allergic inflammation. Failure to develop disease-modifying approaches to therapy will give rise to greater morbidity, mortality and economic burden due to the rapidly increasing incidence of allergic diseases.

References

  1. Malling H-J. Immunotherapy as an effective tool in allergy treatment. Allergy 1998;53:461-72.

  2. Bousquet J, Lockey RF, Malling H-J (Eds): WHO Position Paper. Allergen Immunotherapy: therapeutic vaccines for allergic diseases. Allergy 1998;53 (Suppl 44):1-42.

  3. Purello-DÁmbrosio, Gangemi S, Merendino RA et al. Prevention of new sensitizations in monosensitized subjects submitted to specific immunotherapy or not. A retrospective study. Clin Exp Allergy 2001;31:1295-1302.

  4. Møller C, Dreborg S, Ferdousi HA et al. Pollen immunotherapy reduces the development of asthma in children with seasonal rhinoconjunctivitis (the PAT-study). J Allergy Clin Immunol 2002;109:251-6.

  5. Durham SR, Till SJ. Immunologic changes associated with allergen immunotherapy. J Allergy Clin Immunol 1998;102:157-64

  6. Valenta R, Kraft D. Recombinant allergen molecules: tools to study effector cell activation. Immunol Rev. 2001;179:119-27.

  7. Kumar M, Behera AK, Hu J, Lockey RF, Mohapatra SS. IFN-? and IL-12 plasmid DNAs as vaccine adjuvant in a murine model of grass allergy. J Allergy Clin Immunol 2001;108:402-8.

  8. Malling HJ, Abreu-Nogueira J, Alvarez-Cuesta E, et al. Local immunotherapy. Allergy 1998;53:933-44.

  9. Allergic rhinitis and its impact on asthma. ARIA workshop report. J Allergy Clin Immunol 2001;108:S147-336.

  10. Norman PS, Ohman JL, Long AA et al. Treatment of cat allergy with T-cell reactive peptides. Am J Respir Crit Care Med 1996;154:1623-8

  11. Maguire P, Nicodemus C, Robinson D, Aaronson D, Umetsu DT. The safety and efficacy of ALLERVAX CAT in cat allergic patients. Clin Immunol 1999;93:222-31

  12. Larché, M. Inhibition of human T-cell responses by allergen peptides. Immunology 2001;104:377-82.

  13. Haselden BM, Kay AB, Larché M. Peptide-mediated immune response in specific immunotherapy. Int Arch Allergy Immunol 2000;122;229-37.

  14. Kuehr J, Brauburger J, Zielen S et al. Efficacy of combination treatment with anti-IgE plus specific immunotherapy in polysensitized children and adolescents with seasonal allergic rhinitis. J Allergy Clin immunol 2002;109:274-80.

  15. Broide D, Schwarze J, Tighe H, et al. Immunostimulatory DNA sequences inhibit IL-5, eosinophilic inflammation, and airway hyperresponsiveness in mice. J Immunol 1998;161:7054-62.

  16. Creticos PS, Eiden JJ, Balcer SL, et al. Immunostimulatory oligonucleotides conjugated to Amb a 1: Safety, Skin test reactivity, and basophil histamine release. J Allergy Clin Immunol 2000;105; S70

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