IL-33 synergizes with IgE-dependent and IgE-independent agents to promote mast cell and basophil activation

Silver, Matthew R.; Margulis, Alexander R.; Wood, Nancy L.; Goldman, Samuel J.; Kasaian, Marion T.; Chaudhary, Divya

doi:10.1007/s00011-009-0088-5

Cited by 123 publications

(144 citation statements)

References 69 publications

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“…IL-33 augmented the activating effect of IgE and SCF on MC and basophils (Silver et al, 2010). IL-33 induced release of proinflammatory cytokines, especially IL-6, without degranulation from bone marrow-derived MCs (Moulin et al, 2007), and enhanced IL-8 production from human cord blood-derived cultured mast cells stimulated by IgE/antiIgE, but without histamine release .…”

Section: Introductionmentioning

confidence: 95%

Targeting IL-33 in Autoimmunity and Inflammation

Theoharides

Petra

Taracanova

et al. 2015

J Pharmacol Exp Ther

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Section: Introductionmentioning

confidence: 95%

Targeting IL-33 in Autoimmunity and Inflammation

Theoharides

Petra

Taracanova

et al. 2015

J Pharmacol Exp Ther

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“…IL-33 can amplify both Th1 and Th2 responses (44) and can directly induce cytokine production by mast cells (including IL-13 production; ref. 45) or basophils, as well as enhance IgE+Ag-dependent activation of these cells (44)(45)(46). In the presence of IL-13, IL-33 also can promote polarization of alveolar macrophages toward an alternatively activated macrophage phenotype in vitro or in vivo (47).…”

Section: Figurementioning

confidence: 99%

Identification of an IFN-γ/mast cell axis in a mouse model of chronic asthma

Yu¹,

Eckart²,

Morgan³

et al. 2011

J. Clin. Invest.

119

108

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Asthma is considered a Th2 cell-associated disorder. Despite this, both the Th1 cell-associated cytokine IFN-γ and airway neutrophilia have been implicated in severe asthma. To investigate the relative contributions of different immune system components to the pathogenesis of asthma, we previously developed a model that exhibits several features of severe asthma in humans, including airway neutrophilia and increased lung IFN-γ. In the present studies, we tested the hypothesis that IFN-γ regulates mast cell function in our model of chronic asthma. Engraftment of mast cell-deficient Kit W-sh/W-sh mice, which develop markedly attenuated features of disease, with wild-type mast cells restored disease pathology in this model of chronic asthma. However, disease pathology was not fully restored by engraftment with either IFN-γ receptor 1-null (Ifngr1 -/-) or Fcε receptor 1γ-null (Fcer1g -/-) mast cells. Additional analysis, including gene array studies, showed that mast cell expression of IFN-γR contributed to the development of many FcεRIγ-dependent and some FcεRIγ-independent features of disease in our model, including airway hyperresponsiveness, neutrophilic and eosinophilic inflammation, airway remodeling, and lung expression of several cytokines, chemokines, and markers of an alternatively activated macrophage response. These findings identify a previously unsuspected IFN-γ/mast cell axis in the pathology of chronic allergic inflammation of the airways in mice.

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“…3,4,7 Once released, IL-33 rapidly acts via ST2 to activate an inflammatory response by stimulating mast cells and ILC2s to release Th2 cytokines and chemokines. [8][9][10] For example, the eosinophilia and IL-5 release caused by intranasal administration of the fungal allergen Alternaria alternate is abrogated in ST2-deficient mice. 2 A function-blocking anti-mST2 antibody, sufficiently potent to work in vivo would provide an extremely valuable tool to investigate the importance of the ST2-IL-33 pathway in disease models of asthma, and provide significant advantages over other small molecule and genetic deletion approaches.…”

Section: Introductionmentioning

confidence: 99%

Generation of potent mouse monoclonal antibodies to self-proteins using T-cell epitope “tags”

Percival-Alwyn¹,

England²,

Kemp³

et al. 2015

mAbs

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-linked immunosorbent assay; IgG, immunoglobulin G; SDS-PAGE, sodium dodecyl sulfate-polyacrylamide gel; VH, variable region of immunoglobulin heavy chain; VL, variable region of immunoglobulin light chainImmunization of mice or rats with a "non-self" protein is a commonly used method to obtain monoclonal antibodies, and relies on the immune system's ability to recognize the immunogen as foreign. Immunization of an antigen with 100% identity to the endogenous protein, however, will not elicit a robust immune response. To develop antibodies to mouse proteins, we focused on the potential for breaking such immune tolerance by genetically fusing two independent T-cell epitope-containing sequences (from tetanus toxin (TT) and diphtheria toxin fragment A (DTA)) to a mouse protein, mouse ST2 (mST2). Wild-type CD1 mice were immunized with three mST2 tagged proteins (Fc, TT and DTA) and the specific serum response was determined. Only in mice immunized with the T-cell epitope-containing antigens were specific mST2 serum responses detected; hybridomas generated from these mice secreted highly sequence-diverse IgGs that were capable of binding mST2 and inhibiting the interaction of mST2 with its ligand, mouse interleukin (IL)-33 (mIL-33). Of the hundreds of antibodies profiled, we identified five potent antibodies that were able to inhibit IL-33 induced IL-6 release in a mast cell assay; notably one such antibody was sufficiently potent to suppress IL-5 release and eosinophilia infiltration in an Alternaria alternata challenge mouse model of asthma. This study demonstrated, for the first time, that T-cell epitope-containing tags have the ability to break tolerance in wild-type mice to 100% conserved proteins, and it provides a compelling argument for the broader use of this approach to generate antibodies against any mouse protein or conserved ortholog.

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IL-33 synergizes with IgE-dependent and IgE-independent agents to promote mast cell and basophil activation

Abstract: IL-33 amplifies inflammation in both IgE-independent and IgE-dependent responses.

Cited by 123 publications

References 69 publications

Targeting IL-33 in Autoimmunity and Inflammation

Targeting IL-33 in Autoimmunity and Inflammation

Identification of an IFN-γ/mast cell axis in a mouse model of chronic asthma

Generation of potent mouse monoclonal antibodies to self-proteins using T-cell epitope “tags”

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