Many experimental therapies for autoimmune diseases, such as multiple sclerosis (MS), aim to bias T cells towards tolerogenic phenotypes without broad suppression. However, the link between local signal integration in lymph nodes (LNs) and the specificity of systemic tolerance is not well understood. We used intra-LN injection of polymer particles to study tolerance as a function of signals in the LN microenvironment. In a mouse MS model, intra-LN introduction of encapsulated myelin self-antigen and a regulatory signal (rapamycin) permanently reversed paralysis after one treatment during peak disease. Therapeutic effects were myelin-specific, required antigen encapsulation, and were less potent without rapamycin. This efficacy was accompanied by local LN reorganization, reduced inflammation, systemic expansion of regulatory T cells, and reduced T cell infiltration to the central nervous system. Our findings suggest local control over signaling in distinct LNs can promote cell types and functions that drive tolerance that is systemic, but antigen-specific.
Materials that allow modular, defined assembly of immune signals could support a new generation of rationally designed vaccines that promote tunable immune responses. Toward this goal, we have developed the first polyelectrolyte multilayer (PEM) coatings built entirely from immune signals. These immune-PEMs (iPEMs) are self-assembled on gold nanoparticle templates through stepwise electrostatic interactions between peptide antigen and polyanionic toll-like receptor (TLR) agonists that serve as molecular adjuvants. iPEMs do not require solvents or mixing, offer direct control over the composition and loading of vaccine components, and can be coated on substrates at any scale. These films also do not require other structural components, eliminating the potentially confounding effects caused by the inherent immune-stimulatory characteristics of many synthetic polymers. iPEM loading on gold nanoparticle substrates is tunable, and cryoTEM reveals iPEM shells coated on gold cores. These nanoparticles are efficiently internalized by primary dendritic cells (DCs), resulting in activation, selective triggering of TLR signaling, and presentation of the antigens used to assemble iPEMs. In coculture, iPEMs drive antigen-specific T cell proliferation and effector cytokines but not cytokines associated with more generalized inflammation. Compared to mice treated with soluble antigen and adjuvant, iPEM immunization promotes high levels of antigen-specific CD8(+) T cells in peripheral blood after 1 week. These enhancements result from increased DC activation and antigen presentation in draining lymph nodes. iPEM-immunized mice also exhibit a potent recall response after boosting, supporting the potential of iPEMs for designing well-defined vaccine coatings that provide high cargo density and eliminate synthetic film components.
New
vaccine adjuvants that direct immune cells toward specific
fates could support more potent and selective options for diseases
spanning infection to cancer. However, the empirical nature of vaccines
and the complexity of many formulations has hindered design of well-defined
and easily characterized vaccines. We hypothesized that nanostructured
capsules assembled entirely from polyionic immune signals might support
a platform for simple, modular vaccines. These immune-polyelectrolyte
(iPEM) capsules offer a high signal density, selectively expand T
cells in mice, and drive functional responses during tumor challenge.
iPEMs incorporating clinically relevant antigens could improve vaccine
definition and support more programmable control over immunity.
Poly(ethylene glycol) (PEG) hydrogels have been investigated for a number of applications in tissue engineering. The hydrogels can be designed to mimic tissues that have desired chemical and mechanical properties, but their physical structure can hinder cell migration, tissue invasion, and molecular transport. Synthesis of porous PEG hydrogels could improve transport, enhance cell behavior, and increase the surface area available for cell adhesion. Salt leaching methods have been used extensively to generate porous biomaterial scaffolds but have not previously been applied to hydrogels. In this article we describe a modification of traditional salt leaching techniques for application to hydrogels. Salt-saturated polymer precursor solutions are prepared, and salt crystals of a defined size are added before polymerization. The salt crystals are then leached out, resulting in porous hydrogels. Examples are provided for application of this technique to PEG hydrogels. Porous PEG hydrogels were generated with pore sizes ranging from 15 to 86 microm and porosities from 30% to 75%. Porous hydrogels that were incorporated with a cell adhesion peptide supported cell adhesion with morphology varying with pore size. The simple, reproducible technique described here could be used to generate porous hydrogels with controlled pore sizes for applications in tissue engineering.
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