June 29, 2022

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mRNA vaccine treats multiple sclerosis through bystander tolerance inhibition

mRNA vaccine treats multiple sclerosis through bystander tolerance inhibition

mRNA vaccine treats multiple sclerosis through bystander tolerance inhibition. An important function of the immune system is to be able to recognize “self” and “non-self” antigens. Immune tolerance refers to the specific non-responsive state of the immune system to specific antigens. The immune system can effectively recognize self antigens. Autoantigens do not respond, and this process is called autoimmune tolerance.

Once the autoimmune tolerance is broken, the immune system will attack autoantigens to form autoimmune diseases. Antigen-specific immune tolerance therapy can enable autoimmune diseases to selectively induce the body’s own immune tolerance, while retaining the immune response to “non-self” antigens without impairing normal immune function [1].

In the past few decades, various methods (including the use of DNA, synthetic peptides, recombinant proteins, coated nanoparticles or immunomodulatory cell therapy) have been developed to deliver autoimmune antigens [2].

However, transformation is still far off, and clinical trials are progressing slowly, mainly due to the polyclonal complexity of autoimmune diseases, driven by the patient’s unique and diverse autoreactive immune cell pool.

This inter-individual difference makes either individualized treatment for the patient’s autoantigen immune profile, or therapies that mediate bystander tolerance to suppress autoimmune lymphocytes without extensive immunosuppression [3].

The induction and maintenance of peripheral tolerance is based on the presentation of autoantigens by lymphoid antigen presenting cells (APCs). Previously, there have been some explorations on the use of RNA to deliver antigens. In addition, the mRNA vaccine for COVID-19 has recently shined. An initial success.

It further confirms the feasibility of RNA delivery to induce autoimmune tolerance in humans. The Johannes Gutenberg University Medical Center in Mainz, Germany has recently developed a liposome-based mRNA vaccine (mRNA-LPX) that can deliver antigens to CD11c+ APCs residing in lymphatic tissues [4], thereby activating Toll-like receptor (TLR) signaling induces high levels of IFN-α to activate Th1 cell response. By introducing 1-methylpseudouridine (m1Ψ) to replace uridine (U) during in vitro transcription, the TLR7 signal can be weakened and inflammation can be reduced.

On January 8, 2021, the Ugur Sahin team at the Johannes Gutenberg University Medical Center in Mainz, Germany, published an online research paper entitled A noninflammatory mRNA vaccine for treatment of experimental autoimmune encephalomyelitis on Science, using a modified RNA vaccine to The delivery of antigen to CD11c+ APCs effectively inhibited multiple sclerosis in mice without causing inflammation.

 mRNA vaccine treats multiple sclerosis through bystander tolerance inhibition 

The researchers first tested the immunogenicity and translation efficiency of the modified mRNA, and injected the modified and unmodified mRNA encoding the reporter gene firefly luciferase (LUC) into mice intravenously. The results were consistent with previous reports. Unmodified mRNA can induce strong activation of CD11c+ APCs and lymphocytes. In mice treated with modified m1Ψ mRNA, immune cell activation was not observed, and the translation of LUC was significantly increased, and the translation time was also prolonged. This result showed that m1Ψ mRNA can effectively deliver antigen to spleen CD11c+APCs without inflammation.

Furthermore, the researchers constructed an experimental autoimmune encephalomyelitis (EAE) model by expressing MOG35-55 antigen to study the effect of m1Ψ mRNA in autoimmune diseases. After mice were immunized with MOG35-55 mRNA, MOG35-55- T cell receptor transgenic CD4+ T cells were adopted adoptively transferred to the immunized mice, and the expansion was detected.

The results showed that mice in the MOG35-55 m1Ψ mRNA group induced a higher proportion of Treg cells and exhibited stronger inhibitory function. After antigen stimulation in vitro, CD4+ T cells in MOG35-55 m1Ψ mRNA group secreted fewer Th1 effectors (such as IFN-γ, TNF-α, IL-2 and GM-CSF), and were a marker of T cell exhaustion (Such as TIGIT, TIM-3, PD-1, CTLA-4 and LAG-3) are significantly upregulated.

Next, in order to test whether MOG35-55-specific Treg cells inhibit normal immune function, the researchers also immunized mice with MOG35-55 m1Ψ mRNA and ovalbumin (OVA) or influenza hemagglutinin delivered by unmodified mRNA. (HA) antigen, the results showed that OVA-specific T cells expanded in large numbers and showed effector functions. The protective immune response and neutralizing antibody reaction solution of the mice immunized with HA were not damaged, indicating that MOG35-55 m1Ψ mRNA The induced antigen-specific Treg cells will not inhibit the functional immune response to non-myelin antigens.

Importantly, compared with the control group, the administration of MOG35-55 m1Ψ mRNA can block the clinical progression of EAE in mice and improve the clinical symptoms. In the brain and spinal cord, infiltrating CD4+ T cells, MOG35-55 specific CD4+ T cells and The number of CD4+ T cell subpopulations that secrete IFN-γ and IL-17A is greatly reduced, and spinal cord demyelination is also significantly reduced.

In addition, MOG35-55 specific spleen CD4+ T cells CD44 down-regulation, inhibitory molecules (LAG-3, PD-1, CTLA-4, TIGIT and TIM-3, etc.) up-regulation, Treg cell high activation and other characteristics were also detected. In other EAE models (such as autoreactivity against PLP139-151), the disease has also been significantly improved after treatment with m1Ψ mRNA delivery antigen.

mRNA vaccine treats multiple sclerosis through bystander tolerance inhibition
Antigen-encoded m1Ψ mRNA treatment can effectively improve mouse EAE

Finally, the researchers assessed the bystander activity of Treg cells, and immunized MOG35-55 m1Ψ mRNA in another EAE mouse model of autoimmune reactivity against PLP139-151, which also showed a dose-dependent therapeutic effect. PLP139-151 m1 Ψ mRNA treatment is similar, indicating that the bystander suppression effect mediated by Treg cells is strong. The antigen-specific Treg cells were significantly expanded and highly activated, the effector T cell infiltration was reduced, and no signs of spinal cord demyelination were detected.

In addition, no IgG antibodies against MOG35-55 were detected. Further, under the conditions of a complex EAE model driven by multiple pathogenic self-reactive T cell clones (MOG35-55, PLP139-151, PLP178-191, MBP84-104 and MOBP15-36), the treatment of MOG35-55 m1Ψ mRNA It is equally effective.

And through single-cell sequencing to describe the characteristics of antigen-specific T cells, it again shows that m1Ψ mRNA treatment does not delete autoreactive T cells, but expands effector Treg cells to inhibit MOG35-55 specific Th1 that promotes disease The activity of effector T cells such as Th17 and Th17 to maintain immune balance, this function requires the participation of PD-1 and CTLA-4 pathways.

mRNA vaccine treats multiple sclerosis through bystander tolerance inhibition
mRNA vaccine treats multiple sclerosis through bystander tolerance inhibition
m1Ψ mRNA mediates effective treatment through bystander tolerance


This study showed that 1-methylpseudouridine-modified mRNA (m1Ψ mRNA) formulated with nanoparticles can deliver disease-related autoantigens to the spleen CD11c+ APCs for antigen presentation without inflammatory background.

In several mouse models of multiple sclerosis, m1Ψ mRNA treatment can effectively inhibit the disease, and the therapeutic effect is related to the reduction of effector T cells and the development of Treg cell subsets.

It is worth noting that these Treg cells exercise a potent bystander immunosuppressive function, thereby improving disease conditions induced by homologous and non-homologous autoantigens.



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