RNA vaccine for therapy of autoimmune diseases

In this post, I will share with you the results of research paper about the use of the RNA vaccine (noninflammatory messenger RNA vaccine) in animal models of multiple sclerosis (MS) published in Science earlier this year (1). The use of the mRNA vaccine in several mouse models of MS prevented the disease or reduced the severity of the developed disease without systemic immunosuppression. The mRNA vaccine induced the formation of autoantigen-specific regulatory T cells (Treg) and thus autoantigen-specific immune tolerance.

1. What are the characteristics of RNA vaccines?

The idea of ​​vaccination against infectious diseases based on RNA vaccines dates back to the 1990s, when researchers in France (in the current pharmaceutical company Sanofi Pasteur) first used RNA encoding influenza antigen in mice. In the next ten years, work was done on the development of optimal technology for making mRNA carrier nanoparticles.

A significant advantage of RNA vaccines is the fast process of making the vaccine. From the genetic sequence of the pathogen, a segment encoding the antigen can be quickly determined, the corresponding mRNA can be synthesized and “packed” into a lipid nanoparticle. The use of mRNA vaccines allows for the rapid implementation of many phases of vaccine research and development as opposed to conventional approaches. The SARS-Cov-2 virus pandemic and the development of RNA vaccines against COVID-19 paved the way for the potential application of this technology for the construction of vaccines against many other infectious diseases (tuberculosis, HIV, malaria), as well as for the improvement of seasonal influenza vaccines with the possibility of making a universal vaccine against any strain of influenza virus without redesigning it every year.

The COVID-19 vaccines, developed by Pfizer/BioNTech and Moderna, contain mRNA that encodes the SARS-CoV-2 surface protein, called a spike, that binds to the receptors on human cells (ACE2 receptor). The mRNA in the lipid nanoparticle enters the cytoplasm of cells, binds to ribosomes and encodes the formation of “spike” proteins and is then degraded. mRNA does not enter the nucleus and there is no possibility of changing the genetic material. “Spike” proteins are presented by antigen presenting cells  (APCs) and trigger an immune response in which T and antibody-producing B lymphocytes participate, which are the immune mechanisms underlying protection against COVID-19.

RNA vaccine

Nature 589, 189-191 (2021) doi: https://doi.org/10.1038/d41586-021-00019-w

2. What are the advantages of treating autoimmune diseases by induction autoantigen-specific immune tolerance

Complex mechanisms of immune tolerance prevent the initiation of an immune response to autoantigens of one’s own cells and tissues. Interruption of immune tolerance results in autoimmune reactions and autoimmune diseases. Autoimmune diseases occur when self-antigens (autoantigens) presented by antigen presenting cells (APCs) are recognized by autoreactive T and B lymphocytes which become are activated, proliferate, produce proinflammatory cytokines and autoantibodies that can damage tissues and disrupt organ function.

Regulatory T lymphocytes (Treg) are one of the subpopulations of T lymphocytes that play a key role in maintaining peripheral tolerance (link), preventing autoimmunity and limiting chronic inflammatory diseases. Decreased or impaired Treg function plays a key role in the development of many autoimmune diseases such as type 1 diabetes, multiple sclerosis (MS), autoimmune hemolytic anemia (AHA), autoimmune thyroid disease (ATD), rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), Sjögren’s syndrome, systemic sclerosis and others.

The therapy of autoimmune diseases by induction of antigen-specific tolerance is the subject of current research. This type of treatment involves the selective induction of tolerance to autoantigens relevant to the autoimmune disease without compromising the normal function of the immune system. Unlike other therapies for autoimmune diseases, there is no development of systemic immunosuppression.

Various approaches to selective induction of autoantigen tolerance have been investigated, including the use of DNA encoding autoantigens, synthetic peptides, recombinant proteins, immunomodulatory cell therapies, but no significant beneficial effects have been achieved in clinical studies. The reasons may be in the complexity of autoimmune diseases mediated by a wide repertoire of autoreactive cells, as well as the existence of interindividual variability that requires personalized treatment.

3. What are the effects of non-inflammatory mRNA vaccine in mice models of multiple sclerosis?

Krienke et al. (1) designed a noninflammatory  mRNA vaccine, which has no adjuvant effect and encodes the synthesis of autoantigens involved in the pathogenesis of experimental autoimmune encephalomyelitis (EAE) in mice, which is an animal model of multiple sclerosis. Nanoparticles carrying mRNA enter the dendritic cells of lymphoid tissues and initiate the expansion of autoantigen-specific Treg that suppress autoreactive effector T lymphocytes, but also Treg that suppress autoreactive T lymphocytes specific for other myelin-specific autoantigens The authors administered a noninflammatory mRNA vaccine in several mouse models of MS and showed that this vaccine prevented disease or reduced disease severity without developing systemic immunosuppression.

Autoimmune diseases, such as multiple sclerosis (MS), occur due to interruption of immune tolerance and tissue damage by autoreactive T lymphocytes. Current therapeutic approaches can cause systemic immunosuppression and side effects, such as an increased risk of infection and malignancy. Ability to control autoreactive T cells without induction systemic immunosuppression is the most important goal in research into new therapeutic approaches in autoimmune diseases, including MS.

The results of the work of Krienke et al. (1) show:

  • Therapeutic effects autoantigen-specific immune tolerance induced by a noninflammatory mRNA vaccine in mouse models of MS which is mediated by effector Treg cells in a manner similar to natural mechanisms of peripheral immune tolerances
  • Method of construction of noninflammatory mRNA with modified nucleosides, where uridine (U) was replaced and 1-methylpseudouridine was inserted (m1Ψ mRNA) thus prevented proinflammatory mRNA activity
  • Noninflammatory mRNA (m1Ψ mRNA) encodes autoantigens involved in the pathogenesis of EAE in mice (myelin oligodendrocyte glycoprotein-MOG)
  • The use of m1Ψ mRNA vaccine in several mouse models of MS prevented disease or reduced the severity of the disease without systemic immunosuppression
  • Noninflammatory mRNA (m1Ψ mRNA) reaching CD11c + antigen presenting cells enabled the presentation of autoantigens under tolerogenic conditions, namely in conditions of low expression of costimulatory molecules on APCs
  • Presentation of autoantigens under tolerogenic conditions caused generation CTLA-4 +, ICOS +, IL-10 + Foxp3 + effector Treg cells specific for autoantigens that not only inhibited autoantigen-specific activity of autoreactive Teff cells, but also autoreactive T cells specific to other myelin antigens (bystander immunosuppression)
  • PD-1 and CTLA-4 signaling significantly contributed to induction and maintenance autoantigen-specific tolerance mediated by Treg
  • The use of m1Ψ mRNA reduced the number of effector T cells involved in the pathogenesis of EAE
  • The use of noninflammatory mRNA vaccine did not induce systemic immunosuppression

During the last decade, the use of RNA vaccines other diseases, such as autoimmune and malignant diseases, has been investigated. Scientists believe that the era of RNA vaccines has arrived and an increasing number of leading pharmaceutical companies plan to test various applications of this technology.

Several findings in this paper represent a significant advantages in inducing autoantigen-specific immune tolerance by noninflammatory mRNA that encodes relevant autoantigens as a therapeutic approach in the treatment of autoimmune diseases, in animal models of MS, as an example of a complex autoimmune disease.

Induction of autoantigen-specific immune tolerance using the mRNA vaccine platform may be the basis for potential clinical studies. A particularly significant advantage is the possibility of personalized therapy by selecting mRNAs encoding one or more autoantigens of an individual patient, since any autoantigen can be encoded using the mRNA constructed in this way.

The encouraging results presented in this paper will pave the way for the possibility of the possible application of noninflammatory mRNA vaccine technology in the treatment of autoimmune diseases in humans.

If you have questions, comments and suggestions for topics I will be happy to answer.

Literature

  1. Krienke C, Kolb L, Diken E, Streuber M, Kirchhoff S, Bukur T, Akilli-Öztürk Ö, Kranz      LM, Berger H, Petschenka J, Diken M, Kreiter S, Yogev N, Waisman A, Karikó K, Türeci Ö, Sahin U. A noninflammatory mRNA vaccine for treatment of experimental autoimmune encephalomyelitis. Science. 2021 Jan 8;371(6525):145-153. doi: 10.1126/science.aay3638. PMID: 33414215.
  2. Elie Dolgin. News feature: How COVID unlocked the power of RNA vaccines. Nature 589, 189-191 (2021) doi: https://doi.org/10.1038/d41586-021-00019-w
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