Immunomodulatory Nanoparticles for Modulating Arthritis Flares

Abstract

Disease-modifying drugs have improved the treatment for autoimmune joint disorders, such as rheumatoid arthritis, but inflammatory flares are a common experience. This work reports the development and application of flare-modulating poly(lactic-co-glycolic acid)-poly(ethylene glycol)-maleimide (PLGA-PEG-MAL)-based nanoparticles conjugated with joint-relevant peptide antigens, aggrecan 70−84 and type 2 bovine collagen 256−270 . Peptide-conjugated PLGA-PEG-MAL nanoparticles encapsulated calcitriol, which acted as an immunoregulatory agent, and were termed calcitriol-loaded nanoparticles (CLNP). CLNP had a ∼200 nm hydrodynamic diameter with a low polydispersity index. In vitro, CLNP induced phenotypic changes in bone marrow derived dendritic cells (DC), reducing the expression of costimulatory and major histocompatibility complex class II molecules, and proinflammatory cytokines. Bulk RNA sequencing of DC showed that CLNP enhanced expression of Ctla4, a gene associated with downregulation of immune responses. In vivo, CLNP accumulated in the proximal lymph nodes after intramuscular injection. Administration of CLNP was not associated with changes in peripheral blood cell numbers or cytokine levels. In the collagen-induced arthritis and SKG mouse models of autoimmune joint disorders, CLNP reduced clinical scores, prevented bone erosion, and preserved cartilage proteoglycan, as assessed by high-resolution microcomputed tomography and histomorphometry analysis. The disease protective effects were associated with increased CTLA-4 expression in joint-localized DC and CD4 + T cells but without generalized suppression of T cell-dependent immune response. The results support the potential of CLNP as modulators of disease flares in autoimmune arthropathies.

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

“…We compared model predictions to lymph node and ankle T cell counts in the T cell-driven SKG model of autoimmune arthritis from datasets previously generated and published by our group. 44,45 Comparison of model results to in vivo data showed that T cell proliferation in the lymph node follows a similar trend to model predictions in the range of m = 800–1000 TCR-ad values (Fig. 2g).…”

“…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.…”

“…67–69 The model could be used to simulate the potential efficacy of biomaterial-based strategies that seek to reduce or eliminate pro-inflammatory cytokines or enhance immunoregulatory cell subsets through cytokine delivery. 44,45,70,71…”

“…These include strategies that seek to scavenge pro-inflammatory cytokines or enhance immunoregulatory cell subsets through delivery of small molecules and cytokines. 44,45,70,71,76–78 A key optimization challenge of such agents is the determination of when to apply the therapeutic intervention. Because the cascade of immune activation is complex, suboptimal timing and delivery could result in low efficacy despite robust engineering of the therapeutic.…”

“…To compare the outputs of ABCD of IA with in vivo data, we used previously generated datasets from our group. 44,45 Briefly, arthritis was induced in SKG mice via injection of mannan. Mice were sacrificed on days 1, 5 and 7 following mannan injection.…”