A combination dual-sized microparticle system modulates dendritic cells and prevents type 1 diabetes in prediabetic NOD mice

Abstract

We developed a novel poly(lactic-co-glycolic acid)-based, microparticle (MP) system providing concurrent delivery of multiple encapsulated immuno-suppressive factors and antigen, for in vivo conditioning of dendritic cells (DCs) toward a tolerance promoting pathway. Subcutaneous administration prevents onset of type 1 diabetes (T1D) in NOD mice. Two MP sizes were made: phagocytosable MPs were fabricated encapsulating vitamin D3 or insulin B(9-23) peptide, while unphagocytosable MPs were fabricated encapsulating TGF-β1 or GM-CSF. The combination of Vit D3/ TGF-β1 MPs confers an immature and LPS activation-resistant phenotype to DCs, and MP-delivered antigen is efficiently and functionally presented. Notably, two subcutaneous injections into 4 week old NOD mice using the combination of MPs encapsulating Vit D3, Ins B, TGF-β1 and GM-CSF protected 40% of mice from T1D development, significant in comparison to the control. This work represents one of the first applications of a biomaterial-based, MP vaccine system to successfully prevent autoimmune diabetes.

An antigen-specific semi-therapeutic treatment with local delivery of tolerogenic factors through a dual-sized microparticle system blocks experimental autoimmune encephalomyelitis

“…A similar formulation of the dMP system, encapsulating vitamin D 3 , TGF-β1, and GM-CSF was shown to prevent type 1 diabetes development in NOD mouse when co-delivered with MPs loaded with insulin peptide as antigen in small MPs [41]. This formulation has since been modified by increasing the loading of immunomodulatory factors.…”

“…Thus therapies involving IL-10 may not be optimal given the enhanced immune suppressive effects for bacterial and viral infections. In the current study, TGF-β1, GM-CSF, and vitamin D 3 were chosen as immunomodulatory factors designed to suppress autoimmunity but not cause overwhelming immunosuppression [41, 42]. The regulation of immunity by TGF-β1 is highly intricate and context-dependent where it maintains a delicate balance of tolerogenic versus immunogenic pathways of the immune system while restricting bystander inflammatory tissue damage (reviewed in [84-86]).…”

“…Microparticles (MPs) were fabricated by standard oil-in-water single emulsion or water-in-oil-in-water double emulsion methods, as described previously [41]. All drugs were encapsulated in distinct MPs, as no two factors were loaded simultaneously.…”

“…We have developed a novel combinatorial dual-sized MP system (dMP), encapsulating, in addition to specific antigens, agents selected for their capacity to modulate DC function: both through intracellular delivery of agents encapsulated in small (∼1 μm) MPs, and subcutaneous local deposition of agents for controlled release in MPs too large to phagocytose (∼50 μm) [41, 42]. Our dMP system combines the attractive notion of antigen-specificity and combination therapy with our dual-sized controlled release scheme to provide immune modulation without systemic delivery.…”

“…In sum, the four factors are loaded into separate MPs, with those targeting intracellular pathways in phagocytosable MPs and those targeting surface receptors in non-phagocytosable MPs, hence, dual-sized. We have recently demonstrated the utility of a similar formulation of this multi-factor combinatorial dMP system in the early prevention of autoimmune type 1 diabetes in NOD mice, where a diabetes disease-relevant antigen insulin was incorporated [41]. …”