Conjugation of Transforming Growth Factor Beta to Antigen-Loaded Poly(lactide-co-glycolide) Nanoparticles Enhances Efficiency of Antigen-Specific Tolerance

Abstract

Current strategies for treating autoimmunity involve the administration of broad-acting immunosuppressive agents that impair healthy immunity. Intravenous (i.v.) administration of poly(lactide- co-glycolide) nanoparticles (NPs) containing disease-relevant antigens (Ag-NPs) have demonstrated antigen (Ag)-specific immune tolerance in models of autoimmunity. However, subcutaneous (s.c.) delivery of Ag-NPs has not been effective. This investigation tested the hypothesis that codelivery of the immunomodulatory cytokine, transforming growth factor beta 1 (TGF-β), on Ag-NPs would modulate the immune response to Ag-NPs and improve the efficiency of tolerance induction. TGF-β was coupled to the surface of Ag-NPs such that the loadings of Ag and TGF-β were independently tunable. The particles demonstrated bioactive delivery of Ag and TGF-β in vitro by reducing the inflammatory phenotype of bone marrow-derived dendritic cells and inducing regulatory T cells in a coculture system. Using an in vivo mouse model for multiple sclerosis, experimental autoimmune encephalomyelitis, TGF-β codelivery on Ag-NPs resulted in improved efficacy at lower doses by i.v. administration and significantly reduced disease severity by s.c. administration. This study demonstrates that the codelivery of immunomodulatory cytokines on Ag-NPs may enhance the efficacy of Ag-specific tolerance therapies by programming Ag presenting cells for more efficient tolerance induction.

Potential for Targeting Myeloid Cells in Controlling CNS Inflammation

“…For example, Cappellano et al showed that simultaneous subcutaneous injection of PLGA nanoparticles loaded with either MOG 35−55 or IL-10 ameliorated the course of EAE ( 241 ). TGF-β, another immunoregulatory molecule, coupled to the surface of PLGA nanaopartlces containing PLP 139−151 peptide were shown to improve the tolerogenic effect of Ag-PLGA nanoparticles ( 242 ). Another example is Maldonaldo et al using PLGA nanoparticles loaded PLP 139−151 together with rapamycin, an inhibitor of the mTOR pathway, and demonstrating that a single dose of these particles injected at the peak of disease were able to protect from relapses ( 243 ).…”

Engineering Immune Tolerance with Biomaterials

“…Leveraging this strategy, a number of recent preclinical studies have demonstrated particulate codelivery of self‐antigens and regulatory signals can effectively promote antigen‐specific tolerance . These studies have been conducted in multiple mouse models of autoimmune disease, and in settings aimed at preventing formation of antidrug antibodies against recombinant protein drugs.…”

Biohybrid Nanoparticles to Negotiate with Biological Barriers

“…To develop a T cell activation by targeted delivery, SD‐208 (TGFβR1 inhibitor) encapsulated in PLGA NPs was demonstrated to restore the function of effector T cells . Moreover, incorporation of TGFβ onto the antigen loaded NPs could enhance the efficacy in lower dosage …”