Dataset Information

Tolerogenic Lipid Nanoparticles for Delivering Self-Antigen mRNA for the Treatment of Experimental Autoimmune Encephalomyelitis.

ABSTRACT: Multiple sclerosis is a disease caused by autoantigen-responsive immune cells that disrupt the myelin in the central nervous system (CNS). Although immunosuppressive drugs are used to suppress symptoms, no definitive therapy exists. As in the experimental autoimmune encephalitis (EAE) model of multiple sclerosis, a partial sequence of the myelin oligodendrocyte glycoprotein (MOG_35-55) was identified as a causative autoantigen. This suggests that the induction of immune tolerance that is specific to MOG_35-55 would be a fundamental treatment for EAE. We previously reported that lipid nanoparticles (LNPs) containing an anionic phospholipid, phosphatidylserine (PS), in their lipid composition, can be used to deliver mRNA and that this leads to proteins of interest to be expressed in the spleen. In addition to the targeting capability of PS, PS molecules avoid activating the immune system. Physiologically, the recognition of PS on apoptotic cells suppresses immune activation against these cells by releasing cytokines, such as interleukin-10 (IL-10) and transforming growth factor (TGF)-β that negatively regulate immunity. In this study, we tested whether mRNA delivery of autoantigens to the spleen by PS-LNPs causes the expression of MOG_35-55 antigens with minimal immune stimulation and whether this could be used to treat an EAE model by inducing immune tolerance.

SUBMITTER: Gomi M

PROVIDER: S-EPMC10537621 | biostudies-literature | 2023 Sep

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Tolerogenic Lipid Nanoparticles for Delivering Self-Antigen mRNA for the Treatment of Experimental Autoimmune Encephalomyelitis.

Gomi Masaki M Nakayama Yuka Y Sakurai Yu Y Oyama Ryotaro R Iwasaki Koki K Doi Mizuki M Liu Yi Y Hori Mizuho M Watanabe Himeka H Hashimoto Kohei K Tanaka Hiroki H Tange Kota K Nakai Yuta Y Akita Hidetaka H

Pharmaceuticals (Basel, Switzerland) 20230907 9

Multiple sclerosis is a disease caused by autoantigen-responsive immune cells that disrupt the myelin in the central nervous system (CNS). Although immunosuppressive drugs are used to suppress symptoms, no definitive therapy exists. As in the experimental autoimmune encephalitis (EAE) model of multiple sclerosis, a partial sequence of the myelin oligodendrocyte glycoprotein (MOG<sub>35-55</sub>) was identified as a causative autoantigen. This suggests that the induction of immune tolerance that ...[more]

PMID: 37765078

Similar Datasets

Project description:BackgroundAlthough effective in reducing relapse rate and delaying progression, current therapies for multiple sclerosis (MS) do not completely halt disease progression. T cell autoimmunity to myelin antigens is considered one of the main mechanisms driving MS. It is characterized by autoreactivity to disease-initiating myelin antigen epitope(s), followed by a cascade of epitope spreading, which are both strongly patient-dependent. Targeting a variety of MS-associated antigens by myelin antigen-presenting tolerogenic dendritic cells (tolDC) is a promising treatment strategy to re-establish tolerance in MS. Electroporation with mRNA encoding myelin proteins is an innovative technique to load tolDC with the full spectrum of naturally processed myelin-derived epitopes.MethodsIn this study, we generated murine tolDC presenting myelin oligodendrocyte glycoprotein (MOG) using mRNA electroporation and we assessed the efficacy of MOG mRNA-electroporated tolDC to dampen pathogenic T cell responses in experimental autoimmune encephalomyelitis (EAE). For this, MOG35-55-immunized C57BL/6 mice were injected intravenously at days 13, 17, and 21 post-disease induction with 1α,25-dihydroxyvitamin D3-treated tolDC electroporated with MOG-encoding mRNA. Mice were scored daily for signs of paralysis. At day 25, myelin reactivity was evaluated following restimulation of splenocytes with myelin-derived epitopes. Ex vivo magnetic resonance imaging (MRI) was performed to assess spinal cord inflammatory lesion load.ResultsTreatment of MOG35-55-immunized C57BL/6 mice with MOG mRNA-electroporated or MOG35-55-pulsed tolDC led to a stabilization of the EAE clinical score from the first administration onwards, whereas it worsened in mice treated with non-antigen-loaded tolDC or with vehicle only. In addition, MOG35-55-specific pro-inflammatory pathogenic T cell responses and myelin antigen epitope spreading were inhibited in the peripheral immune system of tolDC-treated mice. Finally, magnetic resonance imaging analysis of hyperintense spots along the spinal cord was in line with the clinical score.ConclusionsElectroporation with mRNA is an efficient and versatile tool to generate myelin-presenting tolDC that are capable to stabilize the clinical score in EAE. These results pave the way for further research into mRNA-electroporated tolDC treatment as a patient-tailored therapy for MS.

Dataset Information

Tolerogenic Lipid Nanoparticles for Delivering Self-Antigen mRNA for the Treatment of Experimental Autoimmune Encephalomyelitis.

Publications

Tolerogenic Lipid Nanoparticles for Delivering Self-Antigen mRNA for the Treatment of Experimental Autoimmune Encephalomyelitis.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets