The ideal treatment for an autoimmune disease should specifically target autoreactive cells, without the need for systemic immune suppression. Various approaches to antigen-specific tolerization of autoreactive T cells have been studied, with limited success. Now, Ugur Sahin and colleagues demonstrate that mRNA-based vaccines not only hold promise for ending the COVID-19 pandemic but can also induce antigen-specific tolerance in mouse models of multiple sclerosis.

The authors had previously developed liposomal formulations of mRNA vaccines (mRNA-LPX) that are optimized for the systemic delivery of mRNA-encoded antigens to lymphoid tissue-resident CD11c+ antigen-presenting cells (APCs). Normally, mRNA vaccination induces strong T helper 1 (TH1) responses via the activation of Toll-like receptors (TLRs). However, mRNA that contains 1-methylpseudouridine (m1Ψ) instead of uracil has strongly reduced inflammatory properties, because the modification abrogates binding to TLR7. The authors hypothesized that vaccination with m1Ψ-modified mRNA (m1Ψ mRNA-LPX) may allow for antigen-presentation by CD11c+ APCs in a non-inflammatory context and thereby induce antigen-specific tolerance.

Credit: Simon Bradbrook/Springer Nature Limited

To test this hypothesis, the authors formulated mRNA, with or without the m1Ψ mutation, with liposomes that lacked adjuvant capacity. Unlike vaccination with mRNA-LPX, m1Ψ mRNA-LPX did not induce inflammatory cytokines or activate immune cells and allowed for higher and prolonged antigen expression.

Next, the modified mRNA was tested in the experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis. In this model, pathology is induced by immunizing mice with a peptide derived from myelin oligodendrocyte glycoprotein (MOG35–55). Mice that were vaccinated with MOG35–55-encoding m1Ψ mRNA on days 7 and 10 after immunization with MOG35–55 were completely protected from disease development. Vaccination of mice with established disease prevented further disease progression and in some cases even reverted pathology.

The authors found that the treatment induced de novo FOXP3+ regulatory T (Treg) cells and enhanced the expression of exhaustion markers such as PD1 and CTLA4 on antigen-specific CD4+ T cells. Importantly, it was also effective in models of EAE induced with a different protein epitope (PLP139–151), indicating that the vaccination can induce bystander tolerance. However, it did not affect immune responses to completely unrelated antigens.

A detailed analysis by single-cell sequencing showed that the m1Ψ mRNA vaccine induces the specific suppression of disease-promoting TH1, TH17 and TH1/TH17 cells by effector Treg cells, rather than the deletion of autoreactive cells. This suppression appeared to be mediated by co-inhibitory molecules, as treatment with PD1-targeted or CTLA4-targeted checkpoint inhibitors almost completely abolished the protective effect of the vaccine.

Vaccination of mice with established disease prevented further disease progression

The authors point out that the m1Ψ mRNA approach is highly flexible, fast and cost efficient. This may allow for the personalization of the vaccine and the combination of different autoantigens.