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

Abstract

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, namely 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 microparticles 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 CD86hiMHCIIhi 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 to mediate antigen-specific tolerance, and suggest that such a multi-factor combinatorial approach can act to block autoimmunity.

Engineering Biomaterials to Direct Innate Immunity

“…[88][89][90][91][92][93][94][95][96][97][98][99][100][101][102][103][104][105][106][107] The hypothesis for this type of strategy is that inhibiting inflammatory signaling or promoting regulatory signaling while antigen is being processed and presented by APCs will promote presentation of antigen in a manner that polarizes effector cells toward tolerance. [88][89][90][91][92][93][94][95][96][97][98][99][100][101][102][103][104][105][106][107] The hypothesis for this type of strategy is that inhibiting inflammatory signaling or promoting regulatory signaling while antigen is being processed and presented by APCs will promote presentation of antigen in a manner that polarizes effector cells toward tolerance.…”

“…[105] This strategy directly targeted the site where innate immune cells converge to program adaptive responses and provided an opportunity to study tolerance induction with respect to the local structure and function of the LN microenvironment. [95,98,99,108] This strategy involves the use of chemical signals (e.g., GM-CSF) to recruit local APCs to the site and regulatory immune signals to facilitate processing of antigen in a tolerogenic manner. An alternative strategy that has been attempted is to establish an artificial microenvironment that attracts APCs to the site and promotes tolerogenic processing of antigen.…”

Engineering Immune Tolerance with Biomaterials

“…In this strategy, depots are engineered to recruit and promote suppressive phenotypes in APCs, which then migrate to draining LNs to polarize tolerogenic immune response generated in these tissues. The Keselowski group designed an immunomodulatory depot system using dual sized microparticles encapsulating self‐antigens and regulatory immune signals . This system involves particles of two different sizes to direct the destination of different components of the therapy.…”

“…Administration of these depots to prediabetic NOD mice significantly decreased the incidence of spontaneous T1D . To apply this platform to promote tolerance in MS models, a similar formulation was tested, but the insulin self‐antigen was exchanged for MOG . Subcutaneous administration of the immune signal loaded dual MPs resulted in the formation of visible nodules at the site of injection with infiltration of mononuclear cells, including DCs, and protein deposition ( Figure A).…”

Direct modulation of myelin-autoreactive CD4⁺ and CD8⁺ T cells in EAE mice by a tolerogenic nanoparticle co-carrying myelin peptide-loaded major histocompatibility complexes, CD47 and multiple regulatory molecules

“…In future, direct and on-target depletion and modulation of autoreactive T cells are worthy to investigate. 24 This study aims to develop a novel tolerogenic NP which functions as a direct modulator of T cells to directly and selectively deplete and/or modulate myelin-autoreactive T cells in the EAE murine model, without the requirement of inducing tolerogenic DCs. Poly(lactic-co-glycolic acid) (PLGA), a biocompatible and biodegradable polymer approved by the Food and Drug Administration and the European Medicines Agency, is widely used in human drug and vaccine delivery systems.…”