immune mechanisms of allergen specific sublingual immunotherapy

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  • Review article

    Immune mechanisms of allergen-specic sublingual

    immunotherapy

    Allergen-specic immunotherapy has been used inhumans for almost a century with the aim to redirectinappropriate immune responses in atopic patients (1, 2).It has proven to be ecacious to treat type I allergies to avariety of allergens (38). While the parenteral (subcuta-neous) route of immunization is still a reference, localroutes (e.g. intranasal, oral) have been considered as analternative with mixed results, both in terms of ecacyand tolerance (9). Of note, a specic form of oraltolerance induction, i.e. sublingual immunotherapy(SLIT) is raising a lot of interest as a noninvasiveprocedure, as it has been shown to be ecacious,provided that high doses of allergen (i.e. 50100-foldthe subcutaneous dose) are administered (1025). In arecent meta-analysis, encompassing 22 clinical studiesevaluating SLIT in 979 patients with allergic rhinitis tohouse dust mite, pollens (from grass, parietaria, olive,ragweed, cupressus) and cat dander, it was concluded thatSLIT signicantly reduces both symptoms and medica-tion requirements (26). Importantly, it is now widelyadmitted that SLIT is much safer than subcutaneousimmunotherapy (SCIT), with no evidence of anaphylacticshock recorded after more than 500 million doses admin-istered to humans (12, 17, 27, 28). Whereas SLIT has

    been successfully used to treat allergic patients, ourunderstanding of the immunological mechanismsinvolved has been limited. We review herein recentscientic advances, which provide some clues on eec-tor/regulatory immune mechanisms elicited during suc-cessful allergen-specic immunotherapy in general, andSLIT in particular. Based on such improved biologicalfoundations, we comment on arising opportunities todesign second-generation sublingual allergy vaccinesrelying upon well-characterized recombinant allergens,capable of controlling T-cell polarization following vac-cine-mediated and subsequent natural exposure to theallergen.

    Immunomodulation during allergen-specific immunotherapy

    As summarized in Fig. 1, allergen-specic immunothera-py, whether it be SCIT or SLIT, is known to reduce bothimmediate as well as late-phase allergen-induced symp-toms, by acting both on humoral, as well as on cellularimmune mechanisms involved in allergic inammation (4,2933). Schematically, three categories of immunologicalchanges are induced by active immunotherapy, encompas-

    Sublingual immunotherapy has been shown in some clinical studies to modulateallergen-specic antibody responses [with a decrease in the immunoglobulin E/immunoglobulin G4 (IgE/IgG4) ratio] and to reduce the recruitment and acti-vation of proinammatory cells in target mucosa. Whereas a central paradigmfor successful immunotherapy has been to reorient the pattern of allergen-spe-cic T-cell responses in atopic patients from a T helper (Th)2 to Th1 prole,there is currently a growing interest in eliciting regulatory T cells, capable ofdownregulating both Th1 and Th2 responses through the production of inter-leukin (IL)-10 and/or transforming growth factor (TGF)-b. We discuss hereinimmune mechanisms involved during allergen-specic sublingual immuno-therapy (SLIT), in comparison with subcutaneous immunotherapy. DuringSLIT, the allergen is captured within the oral mucosa by Langerhans-likedendritic cells expressing high-anity IgE receptors, producing IL-10 and TGF-b, and upregulating indoleamine dioxygenase (IDO), suggesting that such cellsare prone to induce tolerance. The oral mucosa contains limited number ofproinammatory cells, such as mast cells, thereby explaining the well-establishedsafety prole of SLIT. In this context, second-generation vaccines based onrecombinant allergens in a native conformation formulated with adjuvants aredesigned to target Langerhans-like cells in the sublingual mucosa, with the aimto induce allergen-specic regulatory T cells. Importantly, such recombinantvaccines should facilitate the identication of biological markers of SLIT ecacyin humans.

    P. Moingeon1, T. Batard1, R. Fadel1,F. Frati2, J. Sieber3, L. Van Overtvelt11Stallergnes, Antony, France; 2Stallergenes ItaliaS.r.l, Milan, Italy; 3Stallergenes GmbH & Co. KGGermany, Kamp-Lintfort, Germany

    Key words: allergy vaccine; Langerhans cells;regulatory T lymphocyte; sublingual immunotherapy.

    Philippe MoingeonResearch and DevelopmentStallergenes6 rue Alexis de Tocqueville92160 AntonyFrance

    Accepted for publication 5 September 2005

    Allergy 2006: 61: 151165 Copyright Blackwell Munksgaard 2006ALLERGY

    DOI: 10.1111/j.1398-9995.2006.01002.x

    151

  • sing (i) modulation of allergen-specic antibody responses;(ii) reduction in recruitment and activation of proinam-matory cells; and (iii) changes in the pattern of allergen-specic T-cell responses (Table 1). Although such biologi-cal changes are usually better documentedwith SCIT, thereare, in this regard, no clear-cut qualitative dierencesbetween SCIT and SLIT, suggesting that immune mech-anisms at play are similar (Table 1).With respect to allergen-specic antibody responses,

    SCIT often induces an initial increase in seric immuno-globulin E (IgE) levels, prior to a subsequent downregu-lation in the following months (3439). In patients allergicto grass pollen, SCIT prevents the seasonal rise in IgEantibodies associated with natural exposure to allergens(37, 39). Moreover, successful SCIT protocols resulting inclinical improvement of patients often elicit allergen-specic IgG responses (mostly IgG1 and IgG4) and in afew reported cases, IgA responses (Table 1) (5, 4044).Similarly, SLIT was shown to increase allergen-specicIgG4 levels comparedwith placebo (10, 11, 13),with amore

    limited impact on specic IgE responses (18). A decrease inthe IgE/IgG4 ratio has been observed in a number of SLITstudies (11, 24, 45), with some exceptions (46). A meta-analysis of six SLIT studies with detailed analysis ofantibody responses concluded on a consistent increase inallergen-specic IgG4 levels (26). Such changes in the IgE/IgG4 ratio were found to correlate with a decrease in thelate-phase skin reaction to the allergen andwith the overallclinical ecacy of the vaccine in some studies (23, 24) butnot all (13, 18). In a recent phase I/II trial with grass pollentablets, SLIT was shown to elicit allergen-specic sericIgAs in a dose-dependent fashion (47) and a smallupregulation of IgA responses was also observed whenSLIT was used in house dust mite allergic patients (45).Altogether, allergen-specic IgG (and IgA) antibodiesinduced by immunotherapy are thought to contribute tothe positive clinical response through distinct and nonexclusive mechanisms: (i) these antibodies can competewith IgEs for binding to the allergen, thereby preventingboth basophil or mastocyte degranulation (3840), as well

    Figure 1. Humoral and cellular immune mechanisms involved in type I allergy and immunotherapy: an integrated view. Allergen-specic immunotherapy deals with the cause of type I allergies, by inducing long-term reorientation of an existing and inappropriateimmune response (associated with Th2 cytokine production, high IgE levels, activation of mast cells, basophils and eosinophils leadingto release of proinammatory mediators such as histamine, eicosanoids and proteases). CD4+ T helper cells (e.g. Th1, Th2 or Tregulatory) stimulated following allergen exposure or desensitization are critical in controlling these various components of theimmune system through the production of distinct cytokines. IL-4 and IL-13 induce IgE class switching, IL-5 supports eosinophilrecruitment and activation, and IL-13 increases mucus production. Regulatory T cells inhibit both Th1 and Th2 responses through theproduction of IL-10 and TGFb. While atopic patients exhibit allergen-specic Th2 CD4+ cells, healthy people rather mount T regresponses when exposed to allergens. Thus, the purpose of allergen-specic immunotherapy is to restore tolerance by shifting T-cellresponses from Th2 to T Reg.

    Moingeon et al.

    152

  • Table1.

    Mod

    ificatio

    nsof

    immun

    olog

    ical

    parametersdu

    ringallergen

    -spe

    cific

    immun

    othe

    rapy

    (SCITan

    dSL

    IT)inhu

    man

    s

    Parameters

    Allergen

    sused

    Commen

    tsRe

    ference

    Allergen

    -spe

    cific

    antib

    ody

    respon

    ses(Ig

    E,IgG1

    ,IgG

    4,IgA)

    Veno

    ms,

    polle

    ns(ra

    gwee

    d,birch,

    grasses,

    parie

    taria

    ,olive),d

    ustmite

    sUs

    edas:

    na

    turalb

    iologicale

    xtracts,

    allergoids

    recombina

    ntprotein(Bet

    v1)

    associated

    with

    anad

    juvant

    (e.g.

    CaPO

    4,Alum

    ,MPL)for

    SCIT

    na

    turalb

    iologicale

    xtracts,

    and

    allergoids

    with

    outan

    yad

    juvant

    for

    SLIT

    Subcutan

    eous

    immun

    othe

    rapy

    Immun

    oglobu

    linisotyp

    es:S

    CITindu

    cesan

    initial

    increa

    se,followed

    byasubseq

    uent

    decrea

    seof

    specificIgEs,a

    swella

    san

    increa

    sein

    allergen

    -spe

    cific

    IgG1

    andIgG4

    .An

    risein

    IgG4

    /IgEratio

    hasbe

    endo

    cumen

    tedwith

    hypo

    allergen

    icform

    sof

    recombina

    ntBe

    tv1(pep

    tidefra

    gmen

    tsan

    dtrimer).In

    somestud

    ies,

    butno

    tall,

    chan

    gesin

    affin

    ityof

    IgG4

    antib

    odiesfortheallergen

    durin

    gim

    mun

    othe

    rapy

    have

    been

    show

    n.A

    mon

    opho

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