CD33 recruitment inhibits IgE-mediated anaphylaxis and desensitizes mast cells to allergen
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
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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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 5

Antigenic liposomes with CD33L desensitize CD33-Tg mice to antigen challenge.

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Antigenic liposomes with CD33L desensitize CD33-Tg mice to antigen chall...
(A) Injection scheme for desensitization to TNP. CD33-Tg mice were used in the TNP-LP-CD33L–treated group (red). Both CD33-Tg and control-Tg mice were used in the 2 untreated groups (black, gray). (B) Changes in rectal temperature induced by treatment or the challenges indicated in A. (C) Injection scheme to determine antigen specificity of desensitization. CD33-Tg mice were used in the OVA-LP-CD33L–treated group (red circles and squares). Both CD33-Tg and control-Tg mice were used in the untreated group (gray circles and squares). (D) Rectal temperature induced by the treatment or challenge illustrated in C. (B and D) Values are plotted as the mean ± SEM. (E) Injection scheme used to evaluate the impact of TNP-LP-CD33L on mast cell frequency and anti–TNP-IgE on mast cells. Control mice received 200 μl PBS. (F) Frequencies of mast cells from peritoneal fluid from mice treated in E. Mast cell frequencies were determined by c-Kit+CD45+PI– cells. (G) In vitro binding of fluorescent TNP-LP (20 μM) to peritoneal mast cells harvested from mice treated as illustrated in C. (H) MFI of fluorescent TNP-LP binding to peritoneal mast cells quantified in G. The background was determined using untreated cells from a naive mouse. (I) Serum anti–TNP-IgE quantified prior to and 6 hours and 24 hours after treatment with TNP-LP-CD33L (450 μg) using CD33-Tg mice sensitized with 10 μg anti–TNP-IgE. Control mice received 200 μl PBS. Data in B were compiled from 2 experiments. Data are representative of 2 (F–H) or 3 (I) independent experiments. **P < 0.01, ***P < 0.001, and ****P < 0.0001, by RM 2-way ANOVA (B), RM 2-way ANOVA followed by Tukey’s test (D), and unpaired, 2-tailed Student’s t test (F–I).