CD33 recruitment inhibits IgE-mediated anaphylaxis and desensitizes mast cells to allergen
Shiteng Duan, … , Reynold A. Panettieri Jr., James C. Paulson
Shiteng Duan, … , Reynold A. Panettieri Jr., James C. Paulson
Published January 15, 2019
Citation Information: J Clin Invest. 2019;129(3):e125456. https://doi.org/10.1172/JCI125456.
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Research Article Immunology

CD33 recruitment inhibits IgE-mediated anaphylaxis and desensitizes mast cells to allergen

Abstract

Allergen immunotherapy for patients with allergies begins with weekly escalating doses of allergen under medical supervision to monitor and treat IgE mast cell–mediated anaphylaxis. There is currently no treatment to safely desensitize mast cells to enable robust allergen immunotherapy with therapeutic levels of allergen. Here, we demonstrated that liposomal nanoparticles bearing an allergen and a high-affinity glycan ligand of the inhibitory receptor CD33 profoundly suppressed IgE-mediated activation of mast cells, prevented anaphylaxis in Tg mice with mast cells expressing human CD33, and desensitized mice to subsequent allergen challenge for several days. We showed that high levels of CD33 were consistently expressed on human skin mast cells and that the antigenic liposomes with CD33 ligand prevented IgE-mediated bronchoconstriction in slices of human lung. The results demonstrated the potential of exploiting CD33 to desensitize mast cells to provide a therapeutic window for administering allergen immunotherapy without triggering anaphylaxis.

Authors

Shiteng Duan, Cynthia J. Koziol-White, William F. Jester Jr., Scott A. Smith, Corwin M. Nycholat, Matthew S. Macauley, Reynold A. Panettieri Jr., James C. Paulson

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Figure 6

CD33 is expressed on human mast cells and inhibits IgE-mediated human airway bronchoconstriction.

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CD33 is expressed on human mast cells and inhibits IgE-mediated human ai...
(A) Flow cytometric analysis of mast cells isolated from discarded human skin (c-KithiFcεRI+ gated on PI–CD45+CD3–CD19–CD56– cells) (left) and overlay of isotype control and anti-CD33 staining of gated mast cells (right). (B) MFI of antibody staining of Siglecs on mast cells isolated from skin that was discarded following surgical procedures (n = 1 to 10 donors). (C) Time course of the percentage of bronchoconstriction of hPCLSs. Lung slices were sensitized with human IgE (4 mg/ml, gray) or anti–TNP-IgE (10 μg/ml, black and red) with recombinant human SCF (200 ng/ml, R&D Systems) overnight. Slices were challenged with anti–human IgE (20 μg/ml, gray), TNP-LP (50 μM, black), or TNP-LP-CD33L (50 μM, red) over a 10-minute period. The airway luminal area over time was compared with the baseline luminal area and expressed as the percentage of bronchoconstriction. Values represent the mean ± SEM. (D) AUC induced by the indicated treatments. AUC values below 0 are plotted as 0. (E) Percentage of bronchoconstriction induced by the indicated agents at 10 minutes. (F) Following stimulation with the indicated reagents, the percentage of bronchoconstriction induced by CCh (0.1 mM) was measured. *P < 0.05 and **P < 0.01, by 1-way ANOVA followed by Tukey’s test (D–F). Gating of skin mast cells in A is representative of the 10 donors. Data in C–F were compiled from 5 or 9 lung slices from 2 donors.