Combinatorial, Microparticle-Based Delivery of Immune Modulators Reprograms the Dendritic Cell Phenotype and Promotes Remission of Collagen-Induced Arthritis in Mice

Abstract

Safe, effective, antigen-specific therapy for rheumatoid arthritis (RA) remains an elusive clinical goal with a few lasting, viable options on the horizon. Existing therapeutic interventions are indiscriminate and inconsistently immunosuppressive, often leaving patients susceptible to infection. Herein, we investigate the use of a dual-sized, microparticle “regulatory vaccine” (REGvac) that passively targets dendritic cells for antigen-specific biomaterial-based immunotherapy of RA. This REGvac employs poly­(d,l-lactic-co-glycolic-acid) (PLGA) microparticles (MPs) encapsulating (i) a dendritic cell chemoattractant, (ii) potent immunosuppressive molecules, (iii) and an RA-relevant autoantigen to provide a multifaceted approach for the treatment of collagen-induced arthritis (CIA), the primary mouse model of RA. Subcutaneous administrations of the REGvac after mice had developed moderate clinical symptoms markedly diminished overt inflammation in the paws, halted cartilage degradation, and restored gait parameters within 56 days after initial treatment. Positron emission tomography imaging corroborated reduction of inflammation in the paws of REGvac-treated mice. In-depth immunological assessments showed a decreased expression of CD80, CD86, and MHC II on CD11c+ dendritic cells in joint-associated lymph nodes. Further, we observed significant increases in conventional regulatory CD25+FOXP3+ T cells, as well as programmed cell death protein-1 (PD-1)-expressing CD4+ T cells in joint-proximal lymph nodes and the spleen. Real-time PCR analysis of joint tissues from treated mice revealed significant decreases in inflammatory cytokine expression (IL-6), while IL-10 mRNA levels were significantly increased. These observations strongly hint toward the induction of multiple tolerogenic mechanisms by administration of this MP regulatory vaccine. With regards to antigen specificity, ex vivo antigen recall assays revealed a lack of response to collagen by CD4+ T cells from the popliteal and inguinal lymph nodes of REGvac-treated mice, contrasting with the proliferative response of CD4+ T cells from CIA+ mice. Taken altogether, our results strongly support the application of this MP regulatory vaccine as a potent, biomaterial-based, antigen-specific therapy for RA.

Covalent Organic Frameworks for Biomedical Applications

“…In addition to development of vaccines, engineering the immune system also involves mimicking cellular and molecular mechanisms present in the immune system. For example, biomaterials can be utilized to mimic immune cells by delivering proteins and small molecules [ 188–193 ] and affect the overall outcome of the disease. Moreover, immune engineering also involves delivery of cells shielded from the immune system for affecting the outcome of different diseases and disorders.…”

“…[ 191 ] Using a microparticle capable of delivering multiple immunosuppressive molecules, it was demonstrated that inflammation in a rheumatoid arthritis mouse model can be decreased. [ 190 ] Similar to the cancer treatments previously described, COFs with the ability to load large payload can also be used to deliver and target specific pathways via drug delivery approaches for preventing inflammation.…”

Biomaterial-based immunotherapeutic strategies for rheumatoid arthritis

“…The incorporation of biomaterials into drug design, or rather drug delivery technology, blunts conventional drug limitations, permitting augmentations in a myriad of ways. Biomaterials are any materials not considered food or drugs that come into contact with tissue [76] and are being routinely investigated in many therapeutic applications including cardiovascular disease [77], neurodegenerative disease [78], cancer [79], vaccines [80], and autoimmunity [81][82][83]. Using biomaterials to engineer drug delivery systems across different scales offers numerous advantages.…”

“…Microparticles can also act to provide safe intracellular delivery of a broad range of biological agents including peptides and nucleic acids [84]. As such, design of novel NPs and MPs is being heavily investigated to specifically alter aberrant immune cell behavior to treat various immune-dysregulated maladies [82][83][84]. Unsurprisingly, researchers have begun investigating the use of biomaterial-based systems to treat RA, given its pathogenesis being highly immune cell-driven [81].…”

Networks of High Aspect Ratio Particles to Direct Colloidal Assembly Dynamics and Cellular Interactions

“…The generation and delivery of mixed particle co-assemblies has been explored to improve the biodistribution and tissue retention of drug carriers and to deliver multiple cargo types with © 2020 Wiley-VCH GmbH independent release rates. [11,45,46] However, the generation of injectable mixed colloidal assemblies with controlled particle suspension dynamics remains a challenge. Based on our results developing MIN6-HARP cellular suspensions, we hypothesized that HARPs could serve as colloidal scaffolds to improve the suspension dynamics of mixed particle systems through HARP network formation and electrostatic interactions between positively charged chit-HARPs and negatively charged microspheres.…”