Abstract
IgE is the key mediator of allergic responses. Omalizumab, an IgE-specific monoclonal antibody that depletes IgE, is effective for treating severe allergic asthma. The need for frequent administration of the expensive drug, however, limits its applications. Taking advantage of T cell memory, adoptive T cell therapy (ACT) targeting IgE-producing cells has the potential to achieve long-term suppression of IgE and relief of symptoms for severe allergic diseases. The transmembrane form of IgE (mIgE), which is present on all IgE-producing cells, serves as an excellent molecular target for ACT that employs chimeric antigen receptors (CARs). Here, we designed and tested CARs that use the extracellular domain of high affinity IgE receptor, FcεRIα, for mIgE recognition. When expressed on Jurkat T cells, FcεRIα-based CARs mediated robust responses in terms of CD69 upregulation to U266 myeloma cells expressing low levels of mIgE. FcεRIα-based CARs specifically recognized cells expressing mIgE, but not cells with secreted IgE captured through Fcε receptors. CAR+ Jurkat cells did not respond to LAD2 mast cells with secreted IgE bound through FcεRI or Ramos cells with secreted IgE bound through FcεRII. Co-culture of CAR+ Jurkat cells and LAD2 mast cells with IgE bound did not trigger LAD2 cell degranulation. The activity of CAR using wild type FcεRIα for mIgE binding was inhibited by the presence secreted IgE, which likely blocked CAR-mIgE interaction. The activities of CARs using low affinity mutants of FcεRIα, however, tolerated secreted IgE at relatively high concentrations. Moreover, primary human CD8+ T cells expressing a low affinity mutant CAR responded to U266 cells with INFγ production and cytotoxicity despite the presence of secreted IgE. The potency, specificity, and robustness of our CAR design, combined with repaid advances in the safety of ACT, hold promise for novel and highly effective cell-based therapies against severe allergic diseases.
Highlights
In recent decades, the prevalence of allergic diseases has increased rapidly in developed countries, with more than 30% of children allergic, up to 10% of children having asthma and allergic rhinitis, and 5–7% of children having food allergies [1]
Jurkat cells expressing M3 and M5 did not show significant responses to U266 or DaudimIgE stimulation (Supplementary Figure 2).Taken together, these results demonstrated that wilde type (WT) and low affinity FcεRIαbased chimeric antigen receptors (CARs) are capable of mediating robust T cell responses to mIgE+ target cells
Compared with mouse-derived single chain variable fragments commonly used for antigen recognition by CARs, FcεRI α chain (FcεRIα), a natural human protein, is unlikely to trigger host immune responses that may lead to low CAR T cell persistence or even systemic anaphylaxis [39]
Summary
The prevalence of allergic diseases has increased rapidly in developed countries, with more than 30% of children allergic, up to 10% of children having asthma and allergic rhinitis, and 5–7% of children having food allergies [1]. Certain severe allergic diseases, such as severe allergic asthma and multiple food allergy, significantly impact quality of life, create heavy social and economic burdens, and cannot be effectively managed with currently available medications. Cross-linking of IgE and FcεRI by allergens triggers the degranulation and release of inflammatory mediators that induce type I hypersensitivity reactions and allergic symptoms. The effectiveness of omalizumab, an IgE-specific monoclonal antibody that depletes IgE, in treating severe allergic asthma clearly demonstrates the virtue of IgE targeting [2, 3]. An approach that can persistently suppress IgE level over long term with a single treatment would be highly desirable
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