Direct modulation of myelin-autoreactive CD4⁺ and CD8⁺ T cells in EAE mice by a tolerogenic nanoparticle co-carrying myelin peptide-loaded major histocompatibility complexes, CD47 and multiple regulatory molecules

Abstract

PurposeNumerous nanomaterials have been reported in the treatment of multiple sclerosis or experimental autoimmune encephalomyelitis (EAE). But most of these nanoscale therapeutics deliver myelin antigens together with toxins or cytokines and underlay the cellular uptake and induction of tolerogenic antigen-presenting cells by which they indirectly induce T cell tolerance. This study focuses on the on-target and direct modulation of myelin-autoreactive T cells and combined use of multiple regulatory molecules by generating a tolerogenic nanoparticle.Materials and methodsPoly(lactic-co-glycolic acid) nanoparticles (PLGA-NPs) were fabricated by co-coupling MOG40–54/H-2Db-Ig dimer, MOG35–55/I-Ab multimer, anti-Fas, PD-L1-Fc and CD47-Fc and encapsulating transforming growth factor-β1. The resulting 217 nm tolerogenic nanoparticles (tNPs) were administered intravenously into MOG35–55 peptide-induced EAE mice, which was followed by the investigation of therapeutic outcomes and the in vivo mechanism.ResultsFour infusions of the tNPs durably ameliorated EAE with a marked reduction of clinical score, neuroinflammation and demyelination. They were distributed in secondary lymphoid tissues, various organs and brain after intravenous injection, with retention over 36 h, and made contacts with CD4+ and CD8+ T cells. Two injections of the tNPs markedly decreased the MOG35–55-reactive Th1 and Th17 cells and MOG40–55-reactive Tc1 and Tc17 cells, increased regulatory T cells, inhibited T cell proliferation and elevated T cell apoptosis in spleen. Transforming growth factor-β1 and interleukin-10 were upregulated in the homogenates of central nervous system and supernatant of spleen cells.ConclusionOur data suggest a novel therapeutic nanoparticle to directly modulate autoreactive T cells by surface presentation of multiple ligands and paracrine release of cytokine in the antigen-specific combination immunotherapy for T cell-mediated autoimmune diseases.

Promising Nanotechnology Approaches in Treatment of Autoimmune Diseases of Central Nervous System

“…Tolerogenic PLGA nanoparticles can also function as on-target and direct modulators of myelin-autoreactive T cells without eliciting the intervention of tolerogenic dendritic cells. Pei et al [97] developed PLGA nanoparticles for the encapsulation of multiple regulatory molecules. More specifically, the TGF-β was encapsulated in nanoparticles that were surface-decorated by multimers of MHC class I and II molecules loaded with myelin peptides to target autoreactive T cells (MOG 40-54 /H-2D b -Ig dimer, MOG 35-55 /I-A b multimer), by the regulatory molecules (anti-Fas, PD-L1-Fc), being capable of inducing apoptosis or dysfunction of the autoreactive T cells bound to the MHC multimers, or by the "self-marker" CD47-Fc, being able to inhibit nanoparticle phagocytosis.…”

Recent Advances in Antigen-Specific Immunotherapies for the Treatment of Multiple Sclerosis

“…Various biomaterials (e.g., polymers, lipids) have been formulated into micro- or nanoparticles, self-assembled into different structures, or formed molecular conjugates with self-antigens (e.g., conjugation of self-antigens with polymers, antibodies, small molecules). Both nanoparticles (NPs) and microparticles (MPs) can be uptaken by APCs thus enhancing the intracellular delivery of myelin antigens and imunnomodulators [ 180 , 181 ].…”

Potential for Targeting Myeloid Cells in Controlling CNS Inflammation

“…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 ). Also, Pei et al aimed to develop PLGA nanoparticles which function as a direct modulator of T cells, without the involvement of APCs ( 244 ). For that purpose, TGF-β1 encapsulated nanoparticles were coupled with target antigens for CD4 and CD8 T cells (MOG 40−54 /H-2D b -Ig dimer and MOG 35−55 /I-A b multimer), regulatory molecules (anti-Fas and PD-L1-Fc) and a “self-marker” CD47-Fc ( 244 ).…”

“…Also, Pei et al aimed to develop PLGA nanoparticles which function as a direct modulator of T cells, without the involvement of APCs ( 244 ). For that purpose, TGF-β1 encapsulated nanoparticles were coupled with target antigens for CD4 and CD8 T cells (MOG 40−54 /H-2D b -Ig dimer and MOG 35−55 /I-A b multimer), regulatory molecules (anti-Fas and PD-L1-Fc) and a “self-marker” CD47-Fc ( 244 ). These particles were injected in EAE mice on day 8, 18, 28, and 38 after immunization with MOG 35−55 , and induced a significant reduction in EAE symptoms that lasted for more than 100 days.…”

“…These particles were injected in EAE mice on day 8, 18, 28, and 38 after immunization with MOG 35−55 , and induced a significant reduction in EAE symptoms that lasted for more than 100 days. Moreover, the authors observed a decrease of T H 1 and T H 17 MOG 35−55 -specific cells as well as T C 1 and T C 17 MOG 40−55 -specific cells, an increase of regulatory T cells, inhibition of T cell proliferation and augmentation of T cell apoptosis in the spleen ( 244 ). In addition to regulating the immune response, PLGA nanoparticles have also been used as a transporter to help in the remyelination process.…”