A noninflammatory mRNA vaccine for treatment of experimental autoimmune encephalomyelitis

TLDR

Controlling autoreactive T cells without systemic immunosuppression is the main goal for autoimmune disease treatment, but safely delivering defined antigens in a noninflammatory context remains a key challenge. Systemic delivery of nanoparticle‑formulated m1Ψ‑modified mRNA encoding disease‑related autoantigens induces antigen presentation by splenic CD11c⁺ cells without costimulatory signals. In multiple mouse models of multiple sclerosis, this m1Ψ‑mRNA treatment suppresses disease, reduces effector T cells, and induces regulatory T cells that provide strong bystander immunosuppression of both cognate and noncognate autoantigens.

Abstract

The ability to control autoreactive T cells without inducing systemic immune suppression is the major goal for treatment of autoimmune diseases. The key challenge is the safe and efficient delivery of pharmaceutically well-defined antigens in a noninflammatory context. Here, we show that systemic delivery of nanoparticle-formulated 1 methylpseudouridine-modified messenger RNA (m1Ψ mRNA) coding for disease-related autoantigens results in antigen presentation on splenic CD11c+ antigen-presenting cells in the absence of costimulatory signals. In several mouse models of multiple sclerosis, the disease is suppressed by treatment with such m1Ψ mRNA. The treatment effect is associated with a reduction of effector T cells and the development of regulatory T cell (Treg cell) populations. Notably, these Treg cells execute strong bystander immunosuppression and thus improve disease induced by cognate and noncognate autoantigens.