Treg-targeted efficient-inducible platform for collagen-induced arthritis treatment

by Selleckchem | Sep 07 2023

Regulatory T cells (Tregs) display great promise in rheumatoid arthritis (RA) therapy. However, their low number and differentiation rate limit their further application in the clinics. In the present study, we first optimized a combination of IL-2, TGF-β and cyclin dependent kinase inhibitor AS2863619 (IL-2/TGF-β/AS), which could induce Tregs with high efficiency in vitro. After the induced Tregs (iTregs) were confirmed to suppress lymphocyte proliferation and pro-inflammatory T help cells (Th1 and Th17) activation, a chitosan-stabilized nanoparticle drug delivery system (NDDS) was developed according to the optimized formula of IL-2/TGF-β/AS. In vivo study, the NDDS was injected into the knees of mice with collagen-induced arthritis (CIA). As a result, the NDDS remarkably reduced the pathological score of the CIA, alleviated the inflammatory cell infiltration and synovial hyperplasia, and minimized cartilage tissue damage in the knee joint of the CIA mice. Mechanically, the NDDS administration promoted Treg differentiation and decreased Th17 production, consequently reversing the ratio of Treg/Th17, and reducing the secretion of TNF-α in the sera, which facilitated to relieve the severity and progression of arthritis. In sum, NDDS capable of efficiently inducing Tregs were constructed successfully and provided a potential platform for treating RA by restoring the equilibrium of Treg/Th17 destroyed in RA.

Comments:

The study you described investigates the potential use of regulatory T cells (Tregs) in the treatment of rheumatoid arthritis (RA). Tregs have shown promise in RA therapy due to their ability to suppress inflammation and regulate immune responses. However, their limited numbers and differentiation rate have hindered their clinical application. This study aimed to address this limitation by optimizing a combination of factors that could efficiently induce Tregs in vitro.

The researchers optimized a combination of interleukin-2 (IL-2), transforming growth factor-beta (TGF-β), and a cyclin-dependent kinase inhibitor called AS2863619 (referred to as IL-2/TGF-β/AS). This optimized combination was found to induce Tregs with high efficiency in laboratory experiments.

Once the induced Tregs (iTregs) were confirmed to possess the ability to suppress the proliferation of lymphocytes and the activation of pro-inflammatory T helper cells (Th1 and Th17), the researchers developed a chitosan-stabilized nanoparticle drug delivery system (NDDS) based on the optimized IL-2/TGF-β/AS formula.

In the in vivo study, the NDDS was injected into the knees of mice with collagen-induced arthritis (CIA), an animal model that mimics certain aspects of RA. The results showed that the NDDS significantly reduced the pathological score of CIA, alleviated inflammatory cell infiltration and synovial hyperplasia, and minimized damage to the cartilage tissue in the knee joint.

Mechanistically, the administration of NDDS promoted the differentiation of Tregs and decreased the production of Th17 cells, thereby restoring the balance between Tregs and Th17 cells, which is disrupted in RA. This rebalancing of the Treg/Th17 ratio and the reduction in TNF-α secretion in the bloodstream contributed to the alleviation of the severity and progression of arthritis.

Overall, this study successfully constructed an NDDS that efficiently induced Tregs and demonstrated its potential as a platform for treating RA. By restoring the disrupted equilibrium between Tregs and pro-inflammatory Th17 cells, this approach holds promise for mitigating inflammation and potentially providing therapeutic benefits in RA.