Treatment with an antigen-specific dual microparticle system reverses advanced multiple sclerosis in mice

Abstract

Antigen-specific therapies hold promise for treating autoimmune diseases such as multiple sclerosis while avoiding the deleterious side effects of systemic immune suppression due to delivering the disease-specific antigen as part of the treatment. In this study, an antigen-specific dual-sized microparticle (dMP) treatment reversed hind limb paralysis when administered in mice with advanced experimental autoimmune encephalomyelitis (EAE). Treatment reduced central nervous system (CNS) immune cell infiltration, demyelination, and inflammatory cytokine levels. Mechanistic insights using single-cell RNA sequencing showed that treatment impacted the MHC II antigen presentation pathway in dendritic cells, macrophages, B cells, and microglia, not only in the draining lymph nodes but also strikingly in the spinal cord. CD74 and cathepsin S were among the common genes down-regulated in most antigen presenting cell (APC) clusters, with B cells also having numerous MHC II genes reduced. Efficacy of the treatment diminished when B cells were absent, suggesting their impact in this therapy, in concert with other immune populations. Activation and inflammation were reduced in both APCs and T cells. This promising antigen-specific therapeutic approach advantageously engaged essential components of both innate and adaptive autoimmune responses and capably reversed paralysis in advanced EAE without the use of a broad immunosuppressant.

ROS-Scavenging Lignin-Based Tolerogenic Nanoparticle Vaccine for Treatment of Multiple Sclerosis

“…Recently, nano- and microparticles have been explored as potential carriers for delivering self-antigens and tolerogenic cues to investigate their potential in the treatment of autoimmune diseases. For example, different types of nanoparticles, including poly­(lactic- co -glycolic acid) (PLGA) nanoparticles (NPs), − lipid NPs, mesoporous silica NPs, and polydopamine NPs, have been investigated for the treatment of MS. Typically, to create tolerogenic nanovaccines, immunosuppressive agents or immunomodulators like rapamycin, dexamethasone, TGF-β1, and vitamin D3, in addition to autoantigens, are loaded in nanoparticles to induce immune tolerance.…”

A combination microparticle strategy for achieving antigen-specific tolerance

“…A report by Kwiatkowski et al. ( 1 ) in this edition of PNAS describes a biomaterials-based strategy to induce tolerance to a peptide frequently used as a model antigen in MS research. This biomaterial vaccine significantly alters numerous immune cell populations in both the vaccine-draining lymph nodes and CNS and, strikingly, is capable of reversing paralysis in a murine model of advanced disease.…”

“…Building upon these findings, Kwiatkowski et al. ( 1 ) present a novel combinatorial materials strategy that takes advantage of both extracellular and intracellular immune modulation to therapeutically treat established MS and reverse hind limb paralysis in an advanced EAE model. Four distinct PLGA microparticle formulations with two distinct sizes were employed ( Fig.…”

“… Schematic of the dual microparticle (dMP) formulations that were loaded with four distinct immunomodulatory agents ( 1 ). …”

“…Kwiatkowski et al. ( 1 ) demonstrated both reversal of paralysis that results from advanced disease in a murine model of MS and a dramatic alteration in the infiltration and gene expression of immune cells infiltrating the CNS. These findings are consistent with previous work by this research laboratory that demonstrated that this treatment could prevent EAE progression.…”