Fighting against autoimmune diseases is a very challenging task. A novel approach consists of using antigen-specific tolerization that selectively blunt autoimmunity without compromising normal immune function. Physiological induction and maintenance of tolerance is based on the presentation of self-antigens by antigen-presenting cells (APCs) with low level expression of costimulatory molecules. In a recent paper published in Science , Christina Krienke, et al. tried to develop a therapeutic approach that would emulate natural mechanisms of immune tolerance for the treatment of some autoimmune diseases, as they had broad experience introducing liposomal formulation for systemic delivery of messenger RNA (mRNA)-encoded vaccine antigens into APCs. mRNA vaccination induces strong type 1 T helper (Th1) cell responses driven by the IFN-α released from APCs, which is a typical inflammatory signal. Replacement of uridine (U) by incorporation of 1-methylpseudouridine (m1Ψ) and subsequent removal of mRNA contaminants is known to reduce the inflammatory properties of mRNA vaccines . Authors suggested that the use of m1Ψ mRNA for in vitro delivery of autoimmune disease target antigens in a noninflammatory context would enable systemic tolerogenic antigen presentation in lymphoid tissues.
(A and B) Activation of splenic immune cells 24 hours after, and (C) IFN-α serum levels 6 hours after intravenous injection of lipid nanoparticles containing mRNAs and saline control. Whereas U mRNA elicits a high inflammatory response, the m1Ψ mRNA does not. Krienke C, et al. A noninflammatory mRNA vaccine for treatment of experimental autoimmune encephalomyelitis. Science. 2021 Jan 8;371(6525):145-153. doi: 10.1126/science.aay3638
To test their hypothesis, authors first engineered lipid nanoparticles consisting of nonimmunogenic (m1Ψ) or immunogenic (U) mRNA complexes that lack inherent adjuvant activity. mRNA coding for the reporter gene firefly luciferase (LUC) or saline (control) was administered to mice, and the expression of the LUC protein was assessed. Administration of U mRNA led to strong activation of APCs and T lymphocytes and secretion of high levels of IFN α, whereas the m1Ψ mRNA did not induce secretion of IFN-α or any other inflammatory cytokine. Furthermore, LUC expression was profoundly higher and prolonged in m1Ψ mRNA treated animals, suggesting that m1Ψ mRNA is suitable for noninflammatory delivery of proteins into APCs.
Then they wanted to study the effects of m1Ψ mRNA in an autoimmune disease, and chose experimental autoimmune encephalomyelitis (EAE) as a clinical mouse model of multiple sclerosis (MS), in which they previously demonstrated tolerance induction by selectively expressing the epitope of myelin oligodendrocyte glycoprotein MOG35-55 . Mice were immunized with MOG35-55 m1Ψ mRNA or U mRNA and the expansion of T cells was assessed. Both MOG35-55-encoding mRNAs induced proliferation of CD4+ T cells, being m1Ψ mRNA superior, although the functional properties of the induced cells differed profoundly. MOG35-55 m1Ψ mRNA treatment was capable of expanding or inducing de novo T regulatory (Treg) cells that inhibited the in vitro proliferation of antigen-specific naïve CD4+ T cells in a dose-dependent manner. By contrast, T cells of MOG35-55 U mRNA or control-treated mice showed little to no suppressive activity. Whereas MOG35-55 U mRNA-expanded T cells exhibited a functional Th1 effector profile with secretion of inflammatory cytokines, CD4+ T cells from MOG35-55 m1Ψ mRNA-treated mice did not secreted them, even when exposed to very high antigen concentrations.