Journal Article

Immunomodulatory Microparticles Epigenetically Modulate T Cells and Systemically Ameliorate Autoimmune Arthritis

Johnson, Wade T., Nguyen, Anders, Dorn, Nicholas C., Prideaux, Edward B., Kerr, Matthew D., Wang, Wei, Svensson, Mattias N.D., Bottini, Nunzio, Yao, Mina, Zoccheddu, Martina, McBride, David A., Shah, Nisarg J.

2023

Overview

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. This work reports a new intraarticular drug delivery strategy of a disease‐modifying agent that can promote durable disease remission in autoimmune arthritis. The agent protects joints from inflammation‐mediated damage while avoiding generalized suppression of immunity. The systemic effect is attributed to epigenetic modulation of T cells by the agent, which enhances and stabilizes disease‐protective regulatory T cells (Treg). [Image composed in part using BioRender.]

• Publisher: John Wiley & Sons, Inc,John Wiley and Sons Inc,Wiley
• Subject: Acids / Animals / Antirheumatic Agents / Arthritis / Autoimmune Diseases - drug therapy / Autoimmunitet och inflammation / Autoimmunity and Inflammation / Cartilage / Cell culture / Cytokines / immune engineering / Inflammation / Lymphocytes / Mice / regulatory T cells / rheumatoid arthritis / T-Lymphocytes, Regulatory / Tretinoin - pharmacology