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 6

Treatment with allergen-specific mRNA-LNP mitigates asthma responses in mice.

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Treatment with allergen-specific mRNA-LNP mitigates asthma responses in ...
(A) Experimental design. Mice were cutaneously sensitized (gray area) with OVA in the presence of calcipotriol (MC903) daily in the ears for 2 weeks. Immunization (blue area) with LNP or OVA-mRNA-LNP was provided i.m. on days 30 and 37 (blue arrows), followed by 8 airway challenges (pink area and black arrows) with OVA i.t. (daily between day 51 and day 53) and then i.n. (day 58 through day 70). Mice were sacrificed 2 days after last challenge. Naive mice were used as unmanipulated controls. (B) Kinetics of OVA-IgG1, OVA-IgG2a, and OVA-IgE antibody secretion in serum of mice treated with LNP or OVA-mRNA-LNP (n = 16–20). Colored areas indicate treatments as in A. (C) The graphs show quantification of cells in the BALF pooled from 2 independent experiments (n = 7–10). (D) The frequency of GATA3+, Foxp3+, and cytokine-producing cells among CD4+ T cells. (E) A mucus score based on the percentage of PAS staining in the bronchi (n = 9–10). (F) Analysis of the airway resistance in the indicated mice in response to increasing concentrations of methacholine. Data are pooled from 2 independent experiments (n = 6–11). (G) The frequency of perforin+ and CD38+KLRG1– cells among CD8+ T cells in the lungs. (D, E, and G) Data are pooled from 3 independent experiments (n = 10–16). (B and F) Data are mean ± SEM. (C–E and G) 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 or 2-way ANOVA with Tukey correction.