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 2

Clinical outcomes of allergen-specific mRNA-LNP vaccination in acute and chronic asthma models.

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Clinical outcomes of allergen-specific mRNA-LNP vaccination in acute and...
(A) Experimental design. Mice received 2 doses of empty LNP (LNP) or OVA-mRNA-LNP (OVA-mRNA) on days 0 and 7. Mice were OVA+Alum–sensitized on days 24 and 36, and then OVA-challenged i.t. (days 48–49) and i.n. (days 50–51). Mice were sacrificed on day 53. Naive mice served as unmanipulated controls. (B) OVA-specific antibody levels were analyzed 1 week after the second sensitization. Data are pooled from 4 independent experiments (n = 16–20). Data represent individual values, with the mean per group; n.d., not detected. (C) Heatmap of cytokine and chemokine expression in the BALF. Values are normalized per row. (D) Eotaxin-2 levels (ELISA) in BALF (n = 4–10) and eosinophil frequencies in lung tissue (n = 8–17). (E) Airway resistance in response to increasing methacholine doses. Data are pooled from 3 independent experiments (n = 7–12). (F) Representative PAS-stained lung sections show mucus production; arrows indicate mucin-producing goblet cells. Mucus scores were quantified from 4 independent experiments (n = 9–26). Scale bar: 50 μm. (D and F) Box-and-whisker plots. (G) Experimental design. Mice received LNP or OVA-mRNA-LNP on days 0 and 7 and were sensitized on days 24 and 36 and challenged with 9 i.n. OVA doses. Mice were sacrificed on day 71. Naive mice served as unmanipulated controls. (H) Airway resistance was assessed 2 days after the last challenge (n = 4); data are mean ± SEM. Shown is 1 of the 2 replicated experiments. (I) BALF cell counts (n = 9–16). Each dot represents an individual mouse, with group mean shown. (J) Frequencies of lung CD4+ T cell subsets. Box-and-whisker plots summarize findings from 3 independent experiments (n = 9–16). *P ≤ 0.05, **P ≤ 0.01, ****P ≤ 0.0001 by 1-way or 2-way ANOVA with Tukey correction.