Immunomodulatory Microparticles Epigenetically Modulate T Cells and Systemically Ameliorate Autoimmune Arthritis

Abstract

Disease modifying antirheumatic drugs (DMARDs) have improved the prognosis of autoimmune inflammatory arthritides but a large fraction of patients display partial or nonresponsiveness to front-line DMARDs. Here, an immunoregulatory approach based on sustained joint-localized release of all-trans retinoic acid (ATRA), which modulates local immune activation and enhances disease-protective T cells and leads to systemic disease control is reported. ATRA imprints a unique chromatin landscape in T cells, which is associated with an enhancement in the differentiation of naïve T cells into anti-inflammatory regulatory T cells (T reg ) and suppression of T reg destabilization. Sustained release poly-(lactic-co-glycolic) acid (PLGA)-based biodegradable microparticles encapsulating ATRA (PLGA-ATRA MP) are retained in arthritic mouse joints after intra-articular (IA) injection. IA PLGA-ATRA MP enhance migratory T reg which in turn reduce inflammation and modify disease in injected and uninjected joints, a phenotype that is also reproduced by IA injection of T reg . PLGA-ATRA MP reduce proteoglycan loss and bone erosions in the SKG and collagen-induced arthritis mouse models of autoimmune arthritis. Strikingly, systemic disease modulation by PLGA-ATRA MP is not associated with generalized immune suppression. PLGA-ATRA MP have the potential to be developed as a disease modifying agent for autoimmune arthritis.

Immunomodulatory Nanoparticles for Modulating Arthritis Flares

“…Sample sizes for animal studies were based on prior work with SKG and CIA mice without use of additional statistical estimations. , Results were analyzed where indicated using unpaired Student’s t -test, one or two-way ANOVA, and the Mann–Whitney test; each identified for each individual experiment in the figure legends. Data were analyzed by using Graphpad Prism software.…”

ABCD of IA: A multi-scale agent-based model of T cell activation in inflammatory arthritis

“…54 The dynamics of T cell activation modeled by ABCD of IA are well supported by prior in vivo results from arthritic SKG mice. 44,45 Prior work from animal models has established that activated DCs contribute to the development of IA pathology. 55 Adoptive transfer of autoantigen-primed DCs have been shown to expand disease-specific T cells in the joint-draining lymph node in mice.…”

“…The role of cytokines that promote T reg or Th17 differentiation is well established, which can alleviate or enhance disease respectively. 44,46,50,66 We simulated the role of cytokine-mediated T cell phenotype commitment using the ABCD of IA. The results showed that the persistence of inflammation was influenced by the initial level of Th17-inducing cytokines independent of the amount of arthritogenic antigen.…”

“…[67][68][69] The model could be used to simulate the potential efficacy of biomaterialbased strategies that seek to reduce or eliminate pro-inflammatory cytokines or enhance immunoregulatory cell subsets through cytokine delivery. 44,45,70,71 We also used the ABCD of IA to validate the concept of inhibiting T cell signaling to control T cell activation using iaAPCs. Because the effect of iaAPCs in inhibiting pathogenic T cell proliferation is concentration dependent, the appropriate dose for such a therapy would likely require careful dose titration.…”

“…Parameters for probabilistic T cell differentiation were determined using reported experimental data. 44,46 In this addition to the model, Th17 cells contribute to inflammation and antigen production while T reg cells promote inflammation resolution and prevent tissue damage and subsequent antigen production. To understand how initial inflammation levels influenced outcomes of LNUs we performed a parameter sweep across a range of initial inflammation states.…”