Multicomponent Injectable Hydrogels for Antigen-Specific Tolerogenic Immune Modulation

Abstract

Biomaterial scaffolds that enrich and modulate immune cells in situ can form the basis for potent immunotherapies to elicit immunity or reëstablish tolerance. Here, the authors explore the potential of an injectable, porous hydrogel to induce a regulatory T cell (Treg) response by delivering a peptide antigen to dendritic cells in a noninflammatory context. Two methods are described for delivering the BDC peptide from pore-forming alginate gels in the nonobese diabetic mouse model of type 1 diabetes: encapsulation in poly(lactide-co-glycolide) (PLG) microparticles, or direct conjugation to the alginate polymer. While particle-based delivery leads to antigen-specific T cells responses in vivo, PLG particles alter the phenotype of the cells infiltrating the gels. Following gel-based peptide delivery, transient expansion of endogenous antigen-specific T cells is observed in the draining lymph nodes. Antigen-specific T cells accumulate in the gels, and, strikingly, ≈60% of the antigen-specific CD4⁺ T cells in the gels are Tregs. Antigen-specific T cells are also enriched in the pancreatic islets, and administration of peptide-loaded gels does not accelerate diabetes. This work demonstrates that a noninflammatory biomaterial system can generate antigen-specific Tregs in vivo, which may enable the development of new therapies for the treatment of transplant rejection or autoimmune diseases.

Keywords: alginate hydrogels; antigen-specific tolerance; dendritic cells; immunotherapy; regulatory T cells.