Understanding the Mechanism of Allergen Immunotherapy
Amber Luong, MD, PhD
Over 50 million of people suffer from allergies a year in the United States. Many control their symptoms with over-the-counter medications and avoidance measures. A subset of allergy sufferers, approximately 3 million, has found relief with allergen immunotherapy.
Similar to the concept of vaccinations, allergen immunotherapy causes changes in the immune response such that future encounters with the allergen incite mild to no allergy symptoms. The concept of treating hay fever allergies with injections of increasing amounts of ragweed allergen was first documented by Noon in 1911.1 This model has served as the basis of modern day subcutaneous immunotherapy. Since then, a significant amount of information including the specific changes in the immune response to the allergen and immunotherapy has been learned.
The changes to the immune system as a result of immunotherapy can be divided temporally into early, intermediate and late effects. Desensitization of mediator release from mast cells and basophils to allergen exposure is the first change noted with the initiation of allergen immunotherapy. The mechanism responsible for this desensitization has yet to be elucidated. As allergen dosing is increased in the course of immunotherapy, the next most notable response is a change in T cell subset distribution with the generation of allergen specific T regulatory (T reg) cells and a decrease in Th2 cells. Repeated allergen exposure stimulates IL-10 and TGF-β expression by allergen-specific, inducible, type 1, peripheral T regulatory (Tr1) cells, which act in an autocrine fashion to further activate these Tr1 cells and initiate peripheral tolerance. Finally, the late changes include decrease in IgE production by B cells and an increase in IgG4 and IgA serum levels. These changes are responsible for the clinical effect of ameliorating allergy symptoms.
One of the key changes resulting from allergen immunotherapy is the generation of T-reg cells resulting in peripheral tolerance. This emphasis on the importance of the production of T-reg cells by immunotherapy represents a new paradigm shift as it was once emphasized that immunotherapy caused a change in the Th1 to Th2 ratio. Comparison of healthy non-allergic to allergic individuals have found higher levels of T reg cells in those non-allergic individuals.3 In addition to the imbalance in the number of T reg to Th2 cells in allergic individuals, the activity of T reg cells from allergy sufferers are less effective in suppressing CD4+ T cells as compared to healthy controls.2 The newly generated T reg cells from immunotherapy have several suppressive mechanisms including the expression of two cytokines, IL-10 and TGF-β.
A key cytokine involved in reversing the immune and inflammatory response to allergens is IL-10. Secreted from the induced T reg cells, IL-10 has shown direct and indirect suppressive activity. For one, IL-10 acts on B cells to induce the immunoglobulin isotype switch from IgE to IgA, IgG4, and IgG1 production. In addition, IL-10 has suppressive effects on mast cells and basophils. Finally, IL-10 suppresses the inflammatory effects caused by mediators released from mast cells, basophils and eosinophils. These key suppressive effects by IL-10 have incited new interest in this molecule not only for allergy treatment but also in its potential role in cancer.
Our own study is consistent with this key role of IL-10 in differentiating between an allergic versus healthy response to an allergen challenge. Comparing the response of peripheral blood mononuclear cells from allergic fungal rhinosinusitis versus healthy control individuals to fungal antigens, only healthy non-allergic individuals responded to the fungal antigen challenges with increases in IL-10 secretion. Additional studies in the AFRS patients will be necessary to determine if increasing IL-10 and T reg cells represents a desired target effect for any future treatment.
Sublingual immunotherapy (SLIT) has gained some recent excitement as an alternative to subcutaneous immunotherapy (SCIT). Unlike subcutaneous immunotherapy that requires administration in a medical facility; sublingual immunotherapy has proven safe enough to be administered at home. Initial safety and efficacy studies have been performed in Europe. The immunologic mechanism of SLIT appears to be similar to SCIT, although the magnitude of the effects is significantly more modest.4 In the United States, SLIT is not FDA approved. However, a number of US studies are underway, which if adopted in the US will result in a significant change in allergy management. This change is likely to happen as it has in Europe. We as other will be following this development.
- Noon L. Prophylactic inoculation against hay fever. Int Arch Allergy Appl Immunol 1953;4:285-8.
- Akdis M, Verhagen J, Taylor A, et al. Immune Responses in Healthy and Allergic Individuals Are Characterized by a Fine Balance between Allergen-specific T Regulatory 1 and T Helper 2 Cells. The Journal of Experimental Medicine 2004;199:1567.
- Ling EM, Smith T, Nguyen XD, et al. Relation of CD4+ CD25+ regulatory T-cell suppression of allergen-driven T-cell activation to atopic status and expression of allergic disease. The Lancet 2004;363:608-15.
- Wilson D, Lima M, Durham S. Sublingual immunotherapy for allergic rhinitis: systematic review and meta-analysis. Allergy 2005;60:4-12.