Abstract
Rheumatoid arthritis (RA) is a disease of the joints that causes decreased quality of life. Mesenchymal stromal cells (MSCs) have immunosuppressive properties, with possible use in the treatment of RA. Similarly, interleukin (IL)-4 has been shown as a potential RA treatment. However, their combination has not been explored before. Therefore, this study aimed to investigate the effect of a combination therapy of MSCs and IL-4 in the treatment of RA, using a murine collagen-induced arthritis (CIA) model. Arthritis was induced in Balb/c mice by two intradermal injections of type II collagen (CII), at days 0 and 21. CIA mice were randomly assigned to four groups; group I received an intravenous injection of mouse bone marrow-derived MSCs, while group II received an intraperitoneal injection of IL-4. Group III received a combined treatment of MSC and IL-4, while group IV served as a CIA diseased control group receiving phosphate buffer saline (PBS). A fifth group of healthy mice served as the normal healthy control. To assess changes induced by different treatments, levels of RA-associated inflammatory cytokines and biomarkers were measured in the serum, knee joints, and synovial tissue, using ELISA and Real Time-qPCR. Histopathological features of knee joints were analyzed for all groups. Results showed that combined MSC and IL-4 treatment alleviated signs of synovitis in CIA mice, reverting to the values of healthy controls. This was evident by the decrease in the levels of rheumatic factor (RF), C-reactive protein (CRP) and anti-nuclear antibodies (ANA) by 64, 80, and 71%, respectively, compared to the diseased group. Moreover, tumor necrosis factor-alpha (TNF- α) and monocyte chemoattractant protein-1 (MCP-1) levels decreased by 63 and 68%, respectively. Similarly, our gene expression data showed improvement in mice receiving combined therapy compared to other groups receiving single treatment, where cartilage oligomeric matrix protein (Comp), tissue inhibitor metalloproteinase-1 (Timp1), matrix metalloproteinase1 (Mmp-1), and IL-1 receptor (Il-1r) gene expression levels decreased by 75, 70, and 78%, respectively. Collectively, treatment with a combined therapy of MSC and IL-4 might have an efficient therapeutic effect on arthritis. Thus, further studies are needed to assess the potential of different MSC populations in conjugation with IL-4 in the treatment of experimental arthritis.
Highlights
Rheumatoid arthritis (RA) is characterized by inflamed joints causing pain, swelling and stiffness
Mesenchymal stromal cells (MSCs) or IL-4 were used as therapy, there was a significant decrease in the rheumatic factor (RF) serum levels compared to the collagen-induced arthritis (CIA) group, by 60% and 49%, respectively (Figure 2A)
On using combined MSCs and IL-4 as a treatment, RF levels in the blood significantly decreased by 64% compared to the CIA group (Figure 2A)
Summary
Rheumatoid arthritis (RA) is characterized by inflamed joints causing pain, swelling and stiffness. It is an autoimmune disease mediated by autoreactive T cells entering the joint tissues and releasing pro-inflammatory cytokines. Inflammatory cytokines promote macrophage and neutrophil infiltration and activation in joint tissues [1]. It has been found that enhancing the frequency and immunosuppressive function of regulatory T cells (Treg) may provide an important therapeutic strategy for RA [2]. RA is one of the most common autoimmune joint diseases and has witnessed significant therapeutic advances in the past decade. Significant progress has been made in RA treatment for obtaining long-term remission-induction, 20–30% of patients with moderate-to-severe
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