A combination hydrogel microparticle-based vaccine prevents type 1 diabetes in non-obese diabetic mice

Abstract

Targeted delivery of self-antigens to the immune system in a mode that stimulates a tolerance-inducing pathway has proven difficult. To address this hurdle, we developed a vaccine based-approach comprised of two synthetic controlled-release biomaterials, poly(lactide-co-glycolide; PLGA) microparticles (MPs) encapsulating denatured insulin (key self-antigen in type 1 diabetes; T1D), and PuraMatrixTM peptide hydrogel containing granulocyte macrophage colony-stimulating factor (GM-CSF) and CpG ODN1826 (CpG), which were included as vaccine adjuvants to recruit and activate immune cells. Although CpG is normally considered pro-inflammatory, it also has anti-inflammatory effects, including enhancing IL-10 production. Three subcutaneous administrations of this hydrogel (GM-CSF/CpG)/insulin-MP vaccine protected 40% of NOD mice from T1D. In contrast, all control mice became diabetic. In vitro studies indicate CpG stimulation increased IL-10 production, as a potential mechanism. Multiple subcutaneous injections of the insulin containing formulation resulted in formation of granulomas, which resolved by 28 weeks. Histological analysis of these granulomas indicated infiltration of a diverse cadre of immune cells, with characteristics reminiscent of a tertiary lymphoid organ, suggesting the creation of a microenvironment to recruit and educate immune cells. These results demonstrate the feasibility of this injectable hydrogel/MP based vaccine system to prevent T1D.

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

“…Desirable key features of particle vaccines for immunotherapy include: control over phagocytosability, delivery of antigen to DCs, and local release of desired agents. Numerous materials have been investigated in particle-based biodegradable drug delivery, with a number of groups investigating vaccines consisting of antigen-loaded particles to target DCs [31-36]. Microparticles (MPs) fabricated from poly(lactic-co-glycolic acid) (PLGA) have been the most investigated vehicles for delivering immunotherapeutics.…”

A cell-based microarray to investigate combinatorial effects of microparticle-encapsulated adjuvants on dendritic cell activation

“…12–15 Exploiting this potential, DCs have been manipulated both ex vivo and in vivo through controlled release schemes 16 to treat a number of diseases such as cancer, 17–19 infection 20,21 and autoimmunity 22 such as type-1 diabetes. 23–25 A next step in DC modulation involves simultaneously providing combinations of multiple different TLR ligands, which is capable of inducing synergistic increases in antigen-specific immune responses. 26 Targeting multiple TLRs may recapitulate in a well-controlled manner, classic adjuvants formulated from attenuated or killed viruses or bacteria, providing an opportunity to more precisely direct DC function.…”

Improving Vaccine and Immunotherapy Design Using Biomaterials

“…In one strategy a hybrid scaffold-particle encapsulated denatured insulin antigen and a peptide hydrogel containing GM-CSF [91]. This hybrid system reduced type 1 diabetes in mice compared to controls; possibly through establishment of a microenvironment that recruits and expands immune cells in granulomas observed during treatment.…”