Allergen-specific mRNA–lipid nanoparticle therapy for prevention and treatment of experimental allergy in mice
Yrina Rochman, Michael Kotliar, Andrea M. Klingler, Mark Rochman, Mohamad-Gabriel Alameh, Jilian R. Melamed, Garrett A. Osswald, Julie M. Caldwell, Jennifer M. Felton, Lydia E. Mack, Julie Hargis, Ian P. Lewkowich, Artem Barski, Drew Weissman, Marc E. Rothenberg
Yrina Rochman, Michael Kotliar, Andrea M. Klingler, Mark Rochman, Mohamad-Gabriel Alameh, Jilian R. Melamed, Garrett A. Osswald, Julie M. Caldwell, Jennifer M. Felton, Lydia E. Mack, Julie Hargis, Ian P. Lewkowich, Artem Barski, Drew Weissman, Marc E. Rothenberg
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Research Article Immunology Inflammation

Allergen-specific mRNA–lipid nanoparticle therapy for prevention and treatment of experimental allergy in mice

Abstract

Allergic diseases have reached epidemic proportions globally, calling attention to the need for better treatment and preventive approaches. Herein, we developed allergen-encoding messenger RNA (mRNA)–lipid nanoparticle (LNP) strategies for both therapy and prevention of allergic responses. Immunization with allergen-encoded mRNA-LNPs modulated T cell differentiation, inhibiting the generation of T helper type 2 and type 17 cells upon allergen exposure in experimental asthma models induced by ovalbumin, and naturally occurring house dust mite (HDM) and the major HDM allergen Der p1. Allergen-specific mRNA-LNP treatment attenuated clinicopathology in both preventive and established allergy models, including reduction in eosinophilia, mucus production, and airway hypersensitivity, while enhancing production of allergen-specific IgG antibodies and maintaining low IgE levels. Additionally, allergen-specific mRNA-LNP vaccines in mice elicited a CD8+CD38+KLRG– T cell response as seen following SARS-CoV-2 mRNA vaccination in humans, underscoring a conserved immune mechanism across species, regardless of the mRNA-encoded protein. Notably, mRNA-LNP vaccination in combination with an mTOR inhibitor reduced the CD8+ T cell response without affecting the vaccine-induced anti-allergic effect in the preventive model of asthma. This technology renders allergen-specific mRNA-LNP therapy a promising approach for prevention and treatment of allergic diseases.

Authors

Yrina Rochman, Michael Kotliar, Andrea M. Klingler, Mark Rochman, Mohamad-Gabriel Alameh, Jilian R. Melamed, Garrett A. Osswald, Julie M. Caldwell, Jennifer M. Felton, Lydia E. Mack, Julie Hargis, Ian P. Lewkowich, Artem Barski, Drew Weissman, Marc E. Rothenberg

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Figure 5

Der p1–mRNA–LNP protects against allergic responses to HDM.

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Der p1–mRNA–LNP protects against allergic responses to HDM. (A) Experime...
(A) Experimental design. Mice were injected with LNP or Der p1–mRNA–LNP on days 0 and 7 (B–F); both groups were sensitized with HDM (day 28) (C–F) and challenged i.n. with naturally purified Der p1 (np-Der p1) protein (C–E) or HDM extract (F) (days 38–41). (B) Box-and-whisker plot of Der p1–IgG1 antibody levels in the serum of naive, LNP, or Der p1–mRNA–LNP–vaccinated mice on day 26 (n = 9–20). (C) Quantification of cells in the BALF on day 2 after the last challenge. (D and F) The frequency of GATA3+ and cytokine-producing cells among CD4+ T cells in the lungs. (E) Representative PAS-stained sections in bronchi and bronchiole for mucus production. Arrows indicate goblet cells producing mucin. The box-and-whisker plot shows a mucus score pooled from 2 independent experiments (n = 6–8). Scale bar: 50 μm. (C, D, and F) Data are pooled from 2 or 3 independent experiments (n = 6–12), the dots represent individual mice, and the line represents the mean per group. *P ≤ 0.05, **P ≤ 0.01, ***P ≤ 0.001, ****P ≤ 0.0001 by 1-way ANOVA with Tukey correction. n.d., not detected.