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 March 1, 2019; First published January 15, 2019
Citation Information: J Clin Invest. 2019;129(3):1387-1401. https://doi.org/10.1172/JCI125456.
View: Text | PDF
Categories: Research Article Immunology Therapeutics

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., Corwin M. Nycholat, Matthew S. Macauley, Reynold A. Panettieri Jr., James C. Paulson

×

Figure 4

Suppression of IgE-mediated anaphylaxis.

Options: View larger image (or click on image) Download as PowerPoint
Suppression of IgE-mediated anaphylaxis. Display of CD33L on antigenic l...
Display of CD33L on antigenic liposomes suppresses PCA and PSA in CD33-Tg mice (Mcpt5-Cre+/–Rosa26-Stopfl/fl-CD33+), but not in control-Tg mice (Mcpt5-Cre– Rosa26-Stopfl/fl-CD33+). Mice bearing 1 or 2 copies of the CD33 transgene were used. In I, Mcpt5-Cre+/– mice expressing human CD33 (CD33-Tg) were crossed with Ptpn6fl/fl mice to yield mice with mast cells expressing CD33 and no Shp-1 (CD33-Tg/Shp-1–KO). (A) Injection scheme for the PCA model. The genotypes of the mice were determined by PCR after the experiments. (B) Representative images of vascular leakage induced by TNP-LP or TNP-LP-CD33L (50 μg) in control-Tg mice. (C) Quantification of local mast cell activation (absorbance at 650 nm) induced by TNP-LP (50 μg, n = 14) or TNP-LP-CD33L (50 μg, n = 28) in control-Tg mice. (D) Representative images of vascular leakage induced by TNP-LP or TNP-LP-CD33L (50 μg) in CD33-Tg mice. (E) Quantification of local mast cell activation (absorbance at 650 nm) induced by TNP-LP (50 μg, n = 21) or TNP-LP-CD33L (50 μg, n =27) in CD33-Tg mice. (F) Injection scheme for the PSA model. (G–I) Decrease in rectal temperature induced by TNP-LP or TNP-LP-CD33L (150 μg) in control-Tg mice (G), CD33-Tg mice (H), and CD33-Tg mice lacking Shp-1 (I) that were sensitized with 10 μg anti–TNP-IgE. (G–I) Values are plotted as the mean ± SEM at the indicated time points. Data are from 1 experiment (G and I) or were compiled from 3 (H) or 9 sets of experiments (C and E). ***P < 0.001 and ****P < 0.0001, by 1-way ANOVA followed by Tukey’s test (C and E), repeated-measures (RM) 2-way ANOVA (G and H), and RM 2-way ANOVA followed by Tukey’s test (I).