Work

Cyclosporine and fedratinib combination therapy via modulating Th17/Treg balance in Rat model of membranous glomerulonephritis

Year: 2024

Type: article

Abstract: A progressive kidney disease associated with inflammation and the immune system is called membrane glomerulonephritis (MGN). The present study investigatedthe combination of cyclosporine and fedratinib on Th17/regulatory T cells (Tregs) in rat models of MGN. Rats were given several doses of anti-Fx1A to induce MGN, and the resultant five groups of rats were fedratinib-cyclosporin receiving PHN rats, fedratinib, cyclosporin, and healthy rats. Following that, the blood's biochemistry was ascertained, and splenocytes were separated to use flow cytometry to look into the proportion of Th17 and Treg cells in the blood. A real-time PCR test was used to assess the corresponding Tregs and Th17 cell transcription factors andtheir related cytokine gene expressions. Finally, serum analysis was employed to indicate serum cytokines signatures of Th17 cells and Tregs through ELISA. The combination of cyclosporine-fedratinib induced noticeably diminished levels of serum total protein, albumin, and urea in rats versus the PHN group. Th17 cell frequency and its related transcription factors and cytokines genes showed increased expression in the PHN model compared to the control group and PHN groups with different treatments. In contrast, Tregs frequency and its related transcription factors and cytokines genes showed decreased expression in the PHN model compared to the control group and PHN groups with different treatments. Serum cytokine assay confirmed gene expression results. The combination of cyclosporine and fedratinib was capable of reducing Th17 cells in favor of Tregs enhancement in PHN rats, suggesting a novel combination therapy in the treatment of MGN. As you can see in the figure, the PHN mouse model was first created. Then, for 28 days, specific doses of fedratinib, cyclosporine, and both of them were administered to different groups of mice daily. Then, spleen and blood samples were taken from mice, and the amount of IL-10, TGF-β, FoxP3, IL-17, IL-21, RORγT, STAT3, TH17, Treg, and biochemistry characters in mice was measured using qRT-PCR, ELISA, flow cytometry, and autoanalyzer techniques. The results showed that the group of PHN mice receiving fedratinib and cyclosporine had reduced inflammatory factors and protein excretion compared to the control group of PHN mice. • MGN, the most common glomerular disease leading to nephrotic syndrome, can occur primarily or secondary to other conditions. • The Th17 lymphocytes play a central role as inflammatory mediators in glomerulonephritis. • The combo of cyclosporine and fedratinib decreased Th17 cells and improved Tregs in PHN rats.

Source: Biochemistry and Biophysics Reports

DOI: 10.1016/j.bbrep.2024.101874