A Biodegradable Nanoparticle Platform for the Induction of Antigen-Specific Immune Tolerance for Treatment of Autoimmune Disease

Abstract

Targeted immune tolerance is a coveted therapy for the treatment of a variety of autoimmune diseases, as current treatment options often involve nonspecific immunosuppression. Intravenous (iv) infusion of apoptotic syngeneic splenocytes linked with peptide or protein autoantigens using ethylene carbodiimide (ECDI) has been demonstrated to be an effective method for inducing peripheral, antigen-specific tolerance for treatment of autoimmune disease. Here, we show the ability of biodegradable poly(lactic-co-glycolic acid) (PLG) nanoparticles to function as a safe, cost-effective, and highly efficient alternative to cellular carriers for the induction of antigen-specific T cell tolerance. We describe the formulation of tolerogenic PLG particles and demonstrate that administration of myelin antigen-coupled particles both prevented and treated relapsing-remitting experimental autoimmune encephalomyelitis (R-EAE), a CD4 T cell-mediated mouse model of multiple sclerosis (MS). PLG particles made on-site with surfactant modifications surpass the efficacy of commercially available particles in their ability to couple peptide and to prevent disease induction. Most importantly, myelin antigen-coupled PLG nanoparticles are able to significantly ameliorate ongoing disease and subsequent relapses when administered at onset or at peak of acute disease, and minimize epitope spreading when administered during disease remission. Therapeutic treatment results in significantly reduced CNS infiltration of encephalitogenic Th1 (IFN-γ) and Th17 (IL-17a) cells as well as inflammatory monocytes/macrophages. Together, these data describe a platform for antigen display that is safe, low-cost, and highly effective at inducing antigen-specific T cell tolerance. The development of such a platform carries broad implications for the treatment of a variety of immune-mediated diseases.

Harnessing Nanoparticles for Immune Modulation

“…A straight-forward approach is to chemically conjugate the desired active molecule to the particle. Peptide antigens have been chemically conjugated to NPs using 1-ethyl-3-(3-dimethy-laminopropyl)carbodiimide (EDC or ECDI) [6,9], which attaches the amine on the target to a carboxylic acid on the particle. Various chemistries, such as Click chemistry or Michael-type addition, are available and their use is based on the chemical groups within the polymer and on the cargo molecule.…”

“…Furthermore, NPs with a charge below −30 mV have been found to have anti-inflammatory properties and when combined with antigen can induce antigen-specific immune tolerance [6,8,9]. This phenomenon is associated with the ability specifically to target scavenger receptors such as MARCO on monocytes and macrophages [6,8,9].…”

“…The latter cells are essential for the daily filtering and phagocytosis of apoptotic cells and other debris from the blood [48,55,56] and these cells are critically associated with the maintenance of peripheral tolerance. The delivery of NPs via the IV route, in the absence of adjuvant, promotes immune tolerance and provides an avenue to modulate circulating inflammatory monocytes [6,8,9].…”

“…Subsequently, several NP-based approaches for the induction of immune tolerance that function via alternative mechanisms have emerged. Some focus on harnessing the natural capabilities of NPs to deliver antigen in a tolerogenic fashion, while other approaches deliver antigen combined with small-molecule immune suppressants or target aryl hydrocarbon receptors to change DC phenotype [5][6][7]9]. Below is a brief discussion of the mechanisms through which NPs have been shown to induce tolerance, with a focus on harnessing NP delivery of antigen without additional immune suppressants or modulating agents.…”

“…Five-hundred-nanometer NPs with negative zeta potential can be harnessed to target circulating monocytes, reducing their potential for causing immune pathology in numerous experimental disease models including West Nile virus (WNV) encephalitis, myocardial infarction, and inflammatory bowel disease (IBD) [8]. The combination of such NPs with specific autoantigens can also be used to restore peripheral immune tolerance in autoimmune models including experimental autoimmune encephalitis (EAE) [5][6][7]9]. In addition, NPs maybe utilized to mop up extraneous circulating inflammatory mediators.…”