Clinical and immunological control of experimental autoimmune encephalomyelitis by tolerogenic dendritic cells loaded with MOG-encoding mRNA

Abstract

Background Although 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. Methods In 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, MOG 35–55 -immunized C57BL/6 mice were injected intravenously at days 13, 17, and 21 post-disease induction with 1α,25-dihydroxyvitamin D 3 -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. Results Treatment of MOG 35–55 -immunized C57BL/6 mice with MOG mRNA-electroporated or MOG 35–55 -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, MOG 35–55 -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. Conclusions Electroporation 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. Electronic supplementary material The online version of this article (10.1186/s12974-019-1541-1) contains supplementary material, which is available to authorized users.

The Ins and Outs of Messenger RNA Electroporation for Physical Gene Delivery in Immune Cell-Based Therapy

“…Only one registered clinical study relies on this technique to redirect T-cell specificity in type 1 diabetes (NCT02117518, Table 2 ). In preparation for clinical translation, tolerogenic DCs electroporated with mRNA-encoding myelin antigens have shown promising results in mouse models for the treatment of multiple sclerosis [ 60 ], warranting the exploration of these findings in clinical trials.…”

Recent Advances in Antigen-Specific Immunotherapies for the Treatment of Multiple Sclerosis

“…Depending on the experimental protocol, the molecules used to induce tolerogenic properties, and the targeted cell population, tolDCs use different mechanisms of regulation to induce tolerance ( Figure 8 ), including conversion to a regulatory T cell phenotype, induction of anergy, and antigen-specific deletion of T cell clones [ 19 , 35 , 150 , 152 , 153 , 154 ]. Lately, their ability to induce regulatory B cells secreting IL-10 has been also demonstrated [ 152 ].…”

“…( B ) The total number of hyperintense white matter spots along the entire spinal cord was quantified as a measure of lesion load in three mice per treatment group. Results are presented as individual scores for hyperintense spots with median [ 154 ].…”

Metformin as a Potential Agent in the Treatment of Multiple Sclerosis

“…Nevertheless, inflammation of the CNS is the main cause of damage in MS. Numerous immunological studies were carried out using experimental encephalomyelitis (EAE) as an animal model of autoimmune inflammatory diseases of CNS resembling MS [ 41 , 42 , 43 ]. Although EAE is not a perfect MS model, it allows a better understanding of the roles of particular immunological pathways potentially involved in a MS course.…”