An antigen-encapsulating nanoparticle platform for TH1/17 immune tolerance therapy

doi:10.1016/j.nano.2016.09.007

Nanomedicine: Nanotechnology, Biology and Medicine

Volume 13, Issue 1, January 2017, Pages 191-200

https://doi.org/10.1016/j.nano.2016.09.007 Get rights and content

Abstract

Tolerogenic nanoparticles (NPs) are rapidly being developed as specific immunotherapies to treat autoimmune disease. However, many NP-based therapies conjugate antigen (Ag) directly to the NP posing safety concerns due to antibody binding or require the co-delivery of immunosuppressants to induce tolerance. Here, we developed Ag encapsulated NPs comprised of poly(lactide-co-glycolide) [PLG(Ag)] and investigated the mechanism of action for Ag-specific tolerance induction in an autoimmune model of T helper type 1/17 dysfunction – relapse-remitting experimental autoimmune encephalomyelitis (R-EAE). PLG(Ag) completely abrogated disease induction in an organ specific manner, where the spleen was dispensable for tolerance induction. PLG(Ag) delivered intravenously distributed to the liver, associated with macrophages, and recruited Ag-specific T cells. Furthermore, programmed death ligand 1 (PD-L1) was increased on Ag presenting cells and PD-1 blockade lessened tolerance induction. The robust promotion of tolerance by PLG(Ag) without co-delivery of immunosuppressive drugs, suggests that these NPs effectively deliver antigen to endogenous tolerogenic pathways.

Graphical Abstract

Section snippets

Nanoparticle production

PLG NPs with surface carboxylate groups and a negative ζ-potential were prepared using an emulsion-solvent evaporation method as previously described.¹⁵ A double emulsion process was employed for Ag encapsulation, whereas a single emulsion process was used for Ag conjugation. Proteolipid peptide or ovalbumin peptide was surface-coupled to PLG NPs using carbodiimide chemistry as previously described.¹⁵ NP size and ζ-potential were measured by dynamic light scattering (DLS) and zeta potential

Nanoparticle efficacy of Ag-encapsulated PLG particles in R-EAE

NPs were synthesized from PLG using a double emulsion process with the anionic surfactant poly(ethylene-alt-maleic anhydride) (PEMA). Ag-encapsulated NPs [PLG(Ag)] had mean diameters of 450 nm to 850 nm and mean surface ζ-potentials of approximately −50 mV, with similar loading and release profiles (Table 1, Figures S1 and S2). I.V. administration of PLG(PLP_139–151) prevented the development of PLP_139–151-induced R-EAE (Figure 1, A). Furthermore, the maintenance of tolerance induced by PLG(Ag) was

Discussion

The restoration or induction of Ag-specific immune tolerance while maintaining the integrity of protective immune responses is crucial for the development of novel Ag-specific therapies. Our results support the use of Ag-encapsulated PLG NPs for tolerance, i.e., non-immunosuppressive Ag-specific strategies for the treatment of autoimmunity (e.g. MS, T1D), with the potential for use in a range of other applications such as allergy, and cell transplantation,³¹ and augmentation of gene and protein

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: Funding Disclosure: Supported in part by the National Institutes of Health Grants EB-013198 (L.D.S. and S.D.M.), NS-026543 (S.D.M.). C.T.H. was supported in part by a fellowship from the National Multiple Sclerosis Society. D.P.M. was supported in part by the National Institute of Diabetes And Digestive And Kidney Diseases (NIDDK) award T32DK077662. W.T.Y was supported by an award from the American Heart Association, Malkin Scholars Program from the Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Ryan Fellowship and the Northwestern University International Institute for Nanotechnology, and Chicago Biomedical Consortium with support from the Searle Funds at the Chicago Community Trust.

: Conflict of interest disclosure: RMP, SDM, and LDS have financial interests in Cour Pharmaceuticals Development Co.

¹: Co-first authors contributed equally to this work.

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Original ArticleAn antigen-encapsulating nanoparticle platform for TH1/17 immune tolerance therapy

Abstract

Graphical Abstract

Section snippets

Nanoparticle production

Nanoparticle efficacy of Ag-encapsulated PLG particles in R-EAE

Discussion

Vaccine

J Hepatol

Immunity

Blood

Immunity

Biomaterials

Immunity

Antigen-specific tolerance strategies for the prevention and treatment of autoimmune disease

Nat Rev Immunol

Overcoming immunological barriers in regenerative medicine

Nat Biotechnol

The challenge of multiple sclerosis: how do We cure a chronic heterogeneous disease?

Ann Neurol

Engineering antigens for in situ erythrocyte binding induces T-cell deletion

Proc Natl Acad Sci

Double-blind pilot trial of oral Tolerization with myelin antigens in multiple sclerosis

Science

Transdermal application of myelin peptides in multiple sclerosis treatment

JAMA Neurol

Preclinical development and first-in-human study of Atx-Ms-1467 for immunotherapy of MS

Neurol Neuroimmunol Neuroinflamm

Antigen-specific tolerance by autologous myelin peptide-coupled cells: a phase 1 trial in multiple sclerosis

Sci Transl Med

Nanoparticle-mediated Codelivery of myelin antigen and a tolerogenic small molecule suppresses experimental autoimmune encephalomyelitis

Proc Natl Acad Sci

Polymeric synthetic nanoparticles for the induction of antigen-specific immunological tolerance

Proc Natl Acad Sci

Targeted immunomodulation using antigen-conjugated nanoparticles

Wiley Interdiscip Rev Nanomed Nanobiotechnol

Liver inflammation abrogates immunological tolerance induced by Kupffer cells

Hepatology

A biodegradable nanoparticle platform for the induction of antigen-specific immune tolerance for treatment of autoimmune disease

ACS Nano

Microparticles bearing encephalitogenic peptides induce T-cell tolerance and ameliorate experimental autoimmune encephalomyelitis

Nat Biotechnol

Original Article
An antigen-encapsulating nanoparticle platform for T_H1/17 immune tolerance therapy