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 4

OVA-mRNA-LNP in combination with mTOR inhibitor reduces inflammation and frequencies of cytotoxic CD8+ T cells in lungs.

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OVA-mRNA-LNP in combination with mTOR inhibitor reduces inflammation and...
(A) Experimental design. Mice received 2 doses of empty LNP (LNP) or OVA-mRNA-LNP vaccine (OVA-mRNA) on days 0 and 7 (blue arrows). Everolimus (EVL) was administered daily from day –2 to day 12 (shaded area). Mice were OVA+Alum–sensitized on days 24 and 36 and subsequently OVA-challenged for 4 consecutive days (days 48–51), 2 i.t. and then 2 i.n. BALF and lung tissue were collected 2 days after the final challenge (day 53). Naive mice served as unmanipulated controls. (B) Frequencies of indicated CD8+ T cells in the lungs. (C) Frequencies of CD4+ cells expressing GATA3 transcription factor in the lungs, and eosinophil count in the BALF. (B and C) Box-and-whisker plots. (D) Analysis of the airway resistance in the indicated mice in response to increasing concentrations of methacholine. Data are pooled from 2 independent experiments (n = 6–10). Data are mean ± SEM. (B–D) Graphs depict data from combined experiments (n = 9–12). (E) H&E staining of the lungs. Shown are representative panels for each group at the same magnification. Scale bar: 50 μm. *P ≤ 0.05, **P ≤ 0.01, ***P ≤ 0.001, ****P ≤ 0.0001 by 1-way or 2-way ANOVA with Tukey correction.