Immunology
Mechanisms of Sublingual Immunotherapy

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Current proposed mechanism of SLIT

Fig. 1 illustrates a hypothetical model of the pathway of allergen and downstream effects of SLIT. In this model, allergen is taken up by submucosal dendritic cells (perhaps oral Langerhans cells), which then migrate to local regional lymphoid tissues, including submandibular and cervical lymph nodes. There, dendritic cells present peptide fragments to allergen-specific T cells in a protolerogenic manner, resulting in inhibition of activation and proli,feration of Th2 cells and stimulation of

Allergen uptake and presentation in SLIT

Some years ago, a series of pharmacodynamic studies by Bagnasco and colleagues15, 16 explored the local and systemic distribution of allergen in vivo after application to the human sublingual region. Radiolabeled Parietaria allergen was tracked, by both local scintillography and plasma radioactivity, to identify the distribution of allergen after sublingual application, compared with oral (swallowed) allergen. Not only was allergen retained within the sublingual space for several hours, with

Downstream immunologic effects of SLIT

In considering the immunologic effects of effective SLIT, it seems prudent to first briefly consider the better-established effects of SCIT.33, 34 SCIT has been shown to have rapid desensitizing effects on mast cells and basophils, providing some protection from anaphylactic responses in days to weeks. Within weeks there is evidence of T-cell tolerance and the induction of regulatory T cells, including cells expressing IL-10 and TGF-β, as well as the prototypic regulatory cell transcription

Antibody effects of SLIT

Allowing for a break with the proposed chronology of events, as outlined earlier for SCIT, most clinical studies have investigated the effect of SLIT on allergen-specific antibody levels. The observed changes do seem to reflect those of SCIT, albeit at a lower magnitude.

In large, randomized, placebo-controlled trials of grass pollen SLIT significant increases in IgG,36 IgG4,14, 37 or IgE-blocking antibody38 have been recorded, becoming significant versus placebo from about 8 weeks of treatment.

T-cell and cytokine responses during SLIT

Data concerning the effects of SLIT on T-cell proliferation, cytokine secretion, and on the induction of putative regulatory T cells have been varied and at times conflicting. As with data concerning antibodies, this situation may be the result of different allergens, doses, and treatment regimens, but in addition, may also reflect the increased complexity and variability of the assays used by different researchers.

Local mucosal effects of SLIT

SCIT has been shown to reduce allergic inflammation at mucosal sites such as the nose and lung, including reductions in mast cell and eosinophil numbers.61, 62 More recently, phenotypic regulatory T cells have been identified in the nasal mucosa of SCIT-treated patients during natural seasonal pollen exposure.63 These regulatory cells likely have direct antiinflammatory or tolerogenic effects within the target organ. Somewhat less is known regarding local mucosal effects of SLIT.

A

Time course and long-term effects of SLIT

The clinical time course of onset of specific immunotherapy can be difficult to measure, especially when aeroallergen exposure can differ from season to season, day to day, and between individuals. A recent study made use of an artificial allergen exposure chamber to expose both grass pollen SLIT and placebo-treated patients to standardized levels of pollen before and then at regular intervals during the course of treatment.69 Moreover, because the study was entirely conducted outside the

Areas of uncertainty and future study

Although the oral Langerhans cell is an attractive candidate for the role of key antigen-presenting cell in SLIT, it is clear, at least from murine studies, that alternative antigen-presenting cells are also likely involved, including other monocyte-derived dendritic cells, macrophages, and potentially B cells.19, 25 Furthermore, the mechanism of allergen uptake by these cells is as yet uncertain. Further clinical studies using adjuvants are needed, particularly in view of their apparent

Summary

On a systemic level, current evidence suggests SLIT shares many mechanistic properties in common with SCIT. Evidence points to similar, although less pronounced, effects on specific IgG, IgE, and IgA. Furthermore, IgG antibodies at least seem to be functional. Effects on the T-cell compartment are less certain, but a picture of regulatory and Th1 cell induction and Th2 inhibition is emerging.

Understanding of the local mucosal mechanisms is rapidly progressing, with evidence accumulating for a

Acknowledgments

The authors are grateful to Dr Pablo Rodríguez del Río for the construction of Fig. 4.

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      These studies provide evidence for long-term disease remission and disease modification consistent with the induction of antigen-specific tolerance. In parallel with these novel clinical data, there have been advances in our understanding of the underlying mechanisms of SLIT that may give rise to putative biomarkers to predict the clinical response [5–8]. The oral cavity is a naturally tolerogenic environment, remaining noninflamed despite being exposed continuously to multiple foreign proteins.

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      Several studies have reported on the preventive effect of immunotherapy in children with allergic rhinitis (AR) because it appears to reduce the development of new allergic sensitizations and/or new-onset asthma.1,2 Today, clear humoral, cellular, and tissue level changes have been documented with AIT,3–5 and its clinical efficacy leads to economic savings after 6 months of treatment.6 In 2011, the centenary of subcutaneous immunotherapy (SCIT) was celebrated7,8; concurrently, it was 25 years ago that the first double-blind, placebo-controlled (DBPC) trial with SLIT was published.9

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    No conflicts of interest to disclose.

    Stephen Durham has received lecture fees and payments for consultancies from ALK Abello, a manufacturer of allergy vaccines, and research grants from ALK Abello via Imperial College London.

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