Victoria Roberts

Background: Rheumatoid Arthritis (RA) is a chronic inflammatory disorder that typically affects smaller joints such as the hands or feet. It is classified as an autoimmune disorder due to the attack on synovial fluid by the immune system. It is the most diagnosed systemic inflammatory arthritis with a prevalence of 1% worldwide and 0.6-1% in the United States. RA is caused by the uncontrolled proliferation, and differentiation of T lymphocytes. Particularly, the increase of T-Helper Cells (TH17) and decrease of T-Regulatory Cells (Treg). This imbalance of T cell in leads to the recruitment of other inflammatory cells to the synovial fluid of the joints, resulting in inflammation and destruction. The current treatment is the use of disease modifying anti-rheumatic drugs (DMARD). These drugs act by reducing inflammation and act as immune system suppressors, but have limitations in long-term use due to the high risk of co-morbidities. Lately, many studies have been exploring the potential of using extracellular vesicles (EVs) secreted from mesenchymal stem cells (MSC) as a novel treatment for RA.

Objective: To explore the use of EVs derived from MSCs as a possible treatment for RA.

Search Methods: An online search in the PubMed database was conducted from 2019-2024 using the following key words: “Rheumatoid Arthritis,” “Mesenchymal Stem Cells.” “Extracellular Vesicles”.

Results: Studies show that the effects of MSCs give on immune cell suppression is relatively the same as the effects given by the current treatment option. MSCs promoted anti-inflammatory effects on test subjects by modulating genes such as FOXP3 and RORyt, which have a critical role in the differentiation of T-Regulator cells and T-Helper cells. Also, MSCs have shown to activate the programmed cell death-1 (PD-1)/PD-ligand 1 (PD-L1) pathway, thereby inhibiting the activation of T cells and stimulating apoptosis. As such, MSCcan control the inflammation seen in RA patients, however there are several challenges in developing cell-based therapy including tumorigenesis. Recent studies suggest using EVs secreted by MSCs as an alternative to MSCs. EVs release molecules that control the high inflammation in the same ways as both MSCs and DMARDS. At high doses, EVs helped with gene regulation of FOXP3 and RORyt, decreased inflammatory interleukins, and increased the anti-inflammatory cytokine TGF-b1. In addition, EVs able to release PD-L1 and promote apoptosis giving the most sustainable affect.

Conclusion: Studies have shown that the use of EVs from MSC are a promising treatment option due to their low formation of co-morbidities and tumorigenesis. EVs can secrete factors and help stop inflammation by controlling the levels of circulating T-Helper Cells, T-Regulatory cells, IL17, IL-1b and TGF-b. Most importantly, EVs can release PD-L1 stopping T cell activation and stimulating apoptosis. The combination of these effects, using EVs as an anti-inflammatory treatment option can help reduce the severity in Rheumatoid Arthritis patients.

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