Birch pollen immunotherapy results in long-term loss of Bet v 1–specific TH2 responses, transient TR1 activation, and synthesis of IgE-blocking antibodies

Möbs, Christian; Ipsen, Henrik; Mayer, Lea; Slotosch, Caroline; Petersen, Arnd; Würtzen, Peter Adler; Hertl, Michael; Pfützner, Wolfgang

doi:10.1016/j.jaci.2012.07.056

Cited by 105 publications

(101 citation statements)

References 67 publications

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“…Likewise, in a Fel d 1 immunotherapy model, it was demonstrated that allergen-specific IgG1 and IgG2a, but not CD4 + T cells, were critical for the alleviation of local and systemic symptoms [19]. In humans, the induction of allergen-specific IgG antibodies, especially of the IgG4 subclass, is a hallmark of SCIT, and its bioactivity to block IgE-allergen interactions has been associated with clinical improvement [20,21,22]. In contrast, Shirinbak et al [23 ]showed that, in mice, the suppression of a Th2-driven airway inflammation after OVA SCIT was not dependent on the induction of IgG or IgA responses, Fcγ-RIIB signalling or B-cell function, but the effect on AHR was not examined.…”

Section: Discussionmentioning

confidence: 99%

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Birch Pollen Immunotherapy in Mice: Inhibition of Th2 Inflammation Is Not Sufficient to Decrease Airway Hyper-Reactivity

Rijt¹,

Gouveia²,

Logiantara³

et al. 2014

Int Arch Allergy Immunol

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Background: Suppression of Th2 cytokine production by allergen-specific Th2 cells is considered to be critical for the suppression of allergic symptoms by subcutaneous immunotherapy. The aim of this study was to develop a mouse model for birch pollen (BP) immunotherapy to elucidate the underlying mechanisms that contribute to the improvement of clinical symptoms. Methods: Mice with BP-induced allergic airway inflammation received weekly subcutaneous immunotherapy (SCIT) injections with BP extract (BPE) adsorbed to alum. The effect of an increasing dose of BPE adsorbed to a fixed concentration of alum on the suppression of airway inflammation and airway hyper-responsiveness (AHR) was determined. After 2, 4, 6 or 8 immunotherapy injections, the mice were rechallenged with the same allergen and all hallmarks of allergic asthma were evaluated. Results: Suppression of the immunological parameters by immunotherapy was dependent on the BPE dose. Two injections were sufficient to suppress IL-4, IL-5, IL-13, IL-10 and IFN-G production, eosinophil recruitment and peribronchial inflammatory infiltrates. BP-specific immunoglobulins were upregulated, but this was not sufficient to reduce AHR. Eight injections were needed to suppress AHR. The gradual reduction in AHR was inversely associated with the increase of BP IgG2a. Conclusions: BP SCIT induces an early suppression of Th2-mediated eosinophilic airway inflammation, but AHR is only effectively reduced after continued SCIT conceivably by allowing IgG2a antibody titres to build up. i 2014 S. Karger AG, Basel

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Section: Discussionmentioning

confidence: 99%

“…This, however, does not automatically result in an improved clinical outcome. In human SCIT, the functional activity of IgG4 seems to be one of the most useful markers at the moment [7,22]. Mice do not produce IgG4 and murine IgG1 is considered to be its murine homologue [30,31].…”

Section: Discussionmentioning

confidence: 99%

Birch Pollen Immunotherapy in Mice: Inhibition of Th2 Inflammation Is Not Sufficient to Decrease Airway Hyper-Reactivity

Rijt¹,

Gouveia²,

Logiantara³

et al. 2014

Int Arch Allergy Immunol

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“…This characteristic probably enables IgG4 to play a crucial role as a "blocking Ab" during tolerance induction (11,(54)(55)(56), but also as a pathogenic Ab in some autoimmune diseases such as pemphigus vulgaris (57). However, it was hitherto unknown if IgG4 production underlies the same selective mechanisms as the other isotypes.…”

Section: Discussionmentioning

confidence: 99%

“…The role of IgG4 in physiologic immune responses and in allergic diseases is under investigation. Some studies have found a negative correlation between IgG4 titers and symptom score (8)(9)(10)(11)(12)(13) and a positive correlation between IgG4 titers and IL-10-secreting APCs (14) following specific immunotherapy. Nouri-Aria et al (15) found that during specific immunotherapy, allergen-specific IgG4 serum levels increase 10-to 100-fold, and they conclude that grass pollen immunotherapy may induce allergen-specific, IL-10-dependent "protective" IgG4 responses.…”

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confidence: 99%

IgG4 and IgE Transcripts in Childhood Allergic Asthma Reflect Divergent Antigen-Driven Selection

Rogosch

Kerzel

Dey

et al. 2014

The Journal of Immunology

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The physiologic function of the “odd” Ab IgG4 remains enigmatic. IgG4 mediates immunotolerance, as, for example, during specific immunotherapy of allergies, but it mediates tissue damage in autoimmune pemphigus vulgaris and “IgG4-related disease.” Approximately half of the circulating IgG4 molecules are bispecific owing to their unique ability to exchange half-molecules. Better understanding of the interrelation between IgG4 and IgE repertoires may yield insight into the pathogenesis of allergies and into potential novel therapies that modulate IgG4 responses. We aimed to compare the selective forces that forge the IgG4 and IgE repertoires in allergic asthma. Using an IgG4-specific RT-PCR, we amplified, cloned, and sequenced IgG4 H chain transcripts of PBMCs from 10 children with allergic asthma. We obtained 558 functional IgG4 sequences, of which 286 were unique. Compared with previously published unique IgE transcripts from the same blood samples, the somatic mutation rate was significantly enhanced in IgG4 transcripts (62 versus 83%; p < 0.001), whereas fewer IgG4 sequences displayed statistical evidence of Ag-driven selection (p < 0.001). On average, the hypervariable CDRH3 region was four nucleotides shorter in IgG4 than in IgE transcripts (p < 0.001). IgG4 transcripts in the circulation of children with allergic asthma reflect some characteristics of classical Ag-driven B2 immune responses but display less indication of Ag selection than do IgE transcripts. Although allergen-specific IgG4 can block IgE-mediated allergen presentation and degranulation of mast cells, key factors that influence the Ag-binding properties of the Ab differ between the overall repertoires of circulating IgG4- and IgE-expressing cells.

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“…Recent studies investigating allergic patients during AIT in very closely netted schedules revealed only a temporary (or even no significant) induction of IL-10-producing type-1 Treg (Tr1) cells and IFN-γ-secreting Th1 cells, whereas a general loss of allergen-specific T cell reactivity was observed as a long-term result, not only of the disease-specific Th2 cells, but also of suppressive Tr1 or Th2-counterbalancing Th1 cells [16,17,18]. Thus, the mouse model of van Rijt mirrors specific effects seen in AIT-treated patients who finally develop an immunological phenotype similar to nonallergic individuals, in whom the T cells are usually unresponsive to allergens and who do not necessarily show significantly increased numbers of Treg cells [16,19].…”

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confidence: 99%

Allergen-Specific Tolerance Induction: Of Mice and Men

Pfützner

2015

Int Arch Allergy Immunol

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Birch pollen immunotherapy results in long-term loss of Bet v 1–specific TH2 responses, transient TR1 activation, and synthesis of IgE-blocking antibodies

Cited by 105 publications

References 67 publications

Birch Pollen Immunotherapy in Mice: Inhibition of Th2 Inflammation Is Not Sufficient to Decrease Airway Hyper-Reactivity

Birch Pollen Immunotherapy in Mice: Inhibition of Th2 Inflammation Is Not Sufficient to Decrease Airway Hyper-Reactivity

IgG4 and IgE Transcripts in Childhood Allergic Asthma Reflect Divergent Antigen-Driven Selection

Allergen-Specific Tolerance Induction: Of Mice and Men

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