1. Immunomodulatory Microparticles Epigenetically Modulate T Cells and Systemically Ameliorate Autoimmune Arthritis
- Author
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McBride, David A, Kerr, Matthew D, Johnson, Wade T, Nguyen, Anders, Zoccheddu, Martina, Yao, Mina, Prideaux, Edward B, Dorn, Nicholas C, Wang, Wei, Svensson, Mattias ND, Bottini, Nunzio, and Shah, Nisarg J
- Subjects
Biomedical and Clinical Sciences ,Immunology ,Autoimmune Disease ,Arthritis ,2.1 Biological and endogenous factors ,Aetiology ,Inflammatory and immune system ,Mice ,Animals ,Autoimmune Diseases ,T-Lymphocytes ,Regulatory ,Inflammation ,Tretinoin ,Antirheumatic Agents ,immune engineering ,regulatory T cells ,rheumatoid 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 (Treg ) and suppression of Treg 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 Treg which in turn reduce inflammation and modify disease in injected and uninjected joints, a phenotype that is also reproduced by IA injection of Treg . 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.
- Published
- 2023