MARCO-Targeting Carboxylated PLG Nanoparticles Promote Tolerance Induction and Suppression of Inflammatory Monocytes

S. Miller, D. Getts, R. Terry, Z. Hunter, D. McCarthy, W. Yap, N. King, L. Shea
Northwestern University Medical School, US

Keywords: nanoparticles, antigen, polymer-based delivery systems


Antigen-containing nanoparticles have been studied for their ability to stimulate immune responses for purposes of vaccination against infectious diseases and tumors. We hypothesized that nanoparticles administered by the i.v. route might serve as surrogates for apoptotic cells, simplifying the induction of tolerance for the treatment of autoimmune diseases, allergic diseases or tissue transplants. We have shown that a single i.v. infusion of CNS myelin peptide antigen encapsulated within 500nm carboxylated nanoparticles (Ag-NP), composed of biodegradable poly(lactide-co-glycolide) (PLG), effectively abrogated development of the relapsing experimental autoimmune encephalomyelitis (R-EAE) model of MS when used prophylactically and ameliorated progression of clinical disease relapses in R-EAE when administered therapeutically by suppressing myelin-specific Th1- and Th17-mediated autoimmune responses, infiltration of inflammatory cells to the CNS, and CNS demyelination. Ag-NP-induced tolerance is mediated by the combined effects of cell-intrinsic anergy and Treg activation. Ag-NP tolerance is dependent on uptake by splenic marginal zone and liver macrophages via a pathway mediated by the macrophage receptor with collagenous structure (MARCO) scavenger receptor. Our findings demonstrate the feasibility of using Ag-NP as a novel, safe and cost-effective means for antigen-specific therapy of MS and other (auto)immune-mediated diseases using an FDA-approved material, PLG, which can be easily manufactured under GMP conditions. We have recently discovered an alternative use of carboxylated PLG particles for regulation of inflammatory diseases. Inflammatory monocyte-derived effector cells play an important role in the pathogenesis of numerous inflammatory diseases. However, no treatment option exists that is capable of modulating these cells specifically. We show that daily infusion of negatively-charged, immune-modifying PLG microparticles (IMPs) over a 4-6 day period, are taken up by circulating inflammatory monocytes in a MARCO-dependent manner. Subsequently, these monocytes no longer trafficked to sites of inflammation; rather, IMP infusion caused their sequestration in the spleen via apoptotic cell clearance mechanisms and ultimately caspase 3-mediated apoptosis. Administration of IMPs in mouse models of myocardial infarction, stroke, thioglycollate-induced peritonitis, as well as lethal flavivirus encephalitis, markedly reduced monocyte accumulation at inflammatory foci, reduced disease symptoms and promoted tissue repair. Together these data highlight the intricate interplay between scavenger receptors, the spleen and inflammatory monocyte function and support the translation of IMPs for therapeutic use in diseases caused or potentiated by inflammatory monocytes. Supported by grants from the Myelin Repair Foundation and NIH grants EB013198 and NS046543