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Sublingual Immunotherapy - Is There a Role?

Mechanisms of Sublingual Immunotherapy


Anthony J. Frew, MD FRCP
Brighton General Hospital
Brighton, United Kingdom

Professor Tony Frew trained in Cambridge , London , Nottingham , Oxford and Stoke-on-Trent. He developed an interest in allergy while working with Professor Barry Kay at the Royal Brompton Hospital, London and undertook post-doctoral research in Vancouver, Canada. After 13 years in Southampton he recently moved to Brighton to set up a new department. His main research interests are the health effects of air pollution, and clinical trials of allergen immunotherapy; he has published over 200 papers in the peer-reviewed literature. Prof Frew has an active clinical practice, in acute general internal medicine, respiratory medicine and clinical allergy. He has served on the EAACI executive committee since 1995 and is currently president of EAACI. He has served on the Professional Education and International Committees of AAAAI, and is Treasurer for his national society (BSACI).

Abstract

Introduction
Specific allergen immunotherapy (SIT) involves the administration of allergen extracts to modify or abolish symptoms associated with atopic allergy. Several mechanisms have been proposed to explain the beneficial effects of SIT. Conventional injection regimes induce allergen-specific IgG antibodies, especially of the IgG4 subclass. It is not clear whether these contribute directly to efficacy, by blocking the allergic response or whether they are an epiphenomenon, unrelated to the true mode of action. T-cells are also affected by SIT, with a reduction in T-cell and eosinophil recruitment in response to allergen challenge, and a shift in the balance of Th1 and Th2 cytokine expression. These changes are thought to reflect induction of IL-10 secreting T-regulatory cells, which would also account for the induction of IgG4 antibodies.

Against this background, what do we know about the way that sublingual immunotherapy (SLIT) may work? Allergens applied to mucosal surfaces are handled differently from allergens given parenterally. This makes sense conceptually, as the immune system needs to respond vigorously to pathogens that manage to penetrate the body's external defences, while it does not need to respond to antigens that are simply sitting on the mucosal surfaces. Consequently the default mode for antigens encountered at the mucosal surface is tolerance.

From work in experimental animals, we know that IgE responses to allergens can be reduced or prevented by prior administration of allergen by the oral or inhalation routes [1]. It is likely that the route of allergen processing and presentation is a critical determinant of the subsequent T-cell response. In naïve mice, locally administered allergen is taken up by mucosal dendritic cells and then presented to T-cells together with IL-12, thereby biasing the response towards a Th1 profile and away from the pro-allergic Th2 profile [2,3]. It is less clear whether this mechanism can suppress established allergic responses, which is the situation that needs to be achieved by SLIT.

When allergen is given by the sublingual route to allergic humans, it is retained in the buccal region much longer than if the allergen is simply placed in the mouth and then swallowed, suggesting that allergens are indeed taken up locally [4]. However, the immunological response to SLIT in humans is relatively modest and most studies have not found any change in specific IgE, specific IgG or T-cell cytokine balance [5]. In some studies, T-cell proliferative responses to allergens and mitogens were attenuated and more IL-10 was produced after SLIT, compared to untreated allergic controls. IL-10 production after SLIT was similar to the level seen in healthy non-atopic control subjects, suggesting that SLIT may restore a more normal pattern of T-cell responses [6].

Ultimately the adoption of SLIT depends more on the demonstration of clinical efficacy rather than proving precisely which mechanism it may work through. Mechanistic studies do have a place in guiding future developments, but in vitro surrogate measures are no substitute for clinical endpoints!

References

1. Holt PG, Batty JE, Turner KJ. Inhibition of specific IgE responses in mice by pre-exposure to inhaled antigen. Immunology 1981; 42:409-417.

2. Macatinia SE, Hosken NA, Litton M, et al. Dendritic cells produce IL-12 and direct the development of Th1 cells from naïve CD4+ T cells. J Exp Med 1993; 177:1199-1204.

3. McMenamin C, Holt PG. The natural immune response to inhaled soluble protein antigens involves MHC class I-restricted CD8+ T-cell-mediated but MHC class II-restricted CD4+ T-cell-dependent immune deviation resulting in suppression of IgE production. J.Exp.Med. 1993; 178:889-99.

4. Bagnasco M, Altrinetti V, Pesce G, Caputo M, Mistrello G, Falagiani P, Canonica GW, Passalacqua G. Pharmacokinetics of Der p2 allergen and derived monomeric allergoid in allergic volunteers. Int Arch Allergy Immunol. 2005;138:197-202.

5. Fanta C, Bohle B, Hirt W, Siemann U, Horak F, Kraft D, Ebner H, Ebner C. Systemic immunological changes induced by administration of grass pollen allergens via the oral mucosa during sublingual immunotherapy. Int. Arch. Allergy Appl. Immunol. 1999; 120:218-24.

6. Ciprandi G, Fenoglio D, Cirillo I, Vizzaccaro A, Ferrera A, Tosca MA, Puppo F. Induction of IL-10 by sublingual immunotherapy for house dust mites: a preliminary report. Ann. Allergy Asthma Immunol. 2005;95:38-44


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