Journal
BIOMATERIALS
Volume 143, Issue -, Pages 79-92Publisher
ELSEVIER SCI LTD
DOI: 10.1016/j.biomaterials.2017.07.029
Keywords
PLGA-microparticles; Drug delivery; Ag-specific; Immunotherapy; EAE; Multiple sclerosis
Funding
- University of Florida Gatorade Trust
- United States Navy, United States Armed Forces Health Professions Scholarship Program, funds medical education
- National Institute of Diabetes and Digestive and Kidney Diseases [R01 DK091658, R01 DK098589]
- [R01 A1133623]
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Antigen-specific treatments are highly desirable for autoimmune diseases in contrast to treatments which induce systemic immunosuppression. A novel antigen-specific therapy has been developed which, when administered semi-therapeutically, is highly efficacious in the treatment of the mouse model for multiple sclerosis, experimental autoimmune encephalomyelitis (EAE). The treatment uses dual-sized, polymeric microparticles (dMPs) loaded with specific antigen and tolerizing factors for intra- and extra-cellular delivery, designed to recruit and modulate dendritic cells toward a tolerogenic phenotype without systemic release. This approach demonstrated robust efficacy and provided complete protection against disease. Therapeutic efficacy required encapsulation of the factors in controlled-release micro particles and was antigen-specific. Disease blocking was associated with a reduction of infiltrating CD4(+) T cells, inflammatory cytokine-producing pathogenic CD4(+) T cells, and activated macrophages and microglia in the central nervous system. Furthermore, CD4(+) T cells isolated from dMP-treated mice were anergic in response to disease-specific, antigen-loaded splenocytes. Additionally, the frequency of CD86(hi)MHCII(hi) Lir dendritic cells in draining lymph nodes of EAE mice treated with Ag-specific dMPs was reduced. Our findings highlight the efficacy of microparticle-based drug delivery platform to mediate antigen-specific tolerance, and suggest that such a multi-factor combinatorial approach can act to block autoimmunity. (C) 2017 Elsevier Ltd. All rights reserved.
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