Abstract
Purpose :
Non-infectious uveitis (NIU) is treated primarily with corticosteroids or non-steroidal immunosuppressive therapy (IST). Nearly a third to half of patients on IST fails to achieve control of uveitis even after one year of treatment. Multi-drug resistance proteins such as P-glycoprotein (P-gp), are transmembrane proteins that allow efflux of intracellular drugs. The aim of our study was to compare P-gp expression between responders and non-responders to IST.
Methods :
We included patients with NIU on IST for ≥3 months and corticosteroid dose ≤10mg/day. Non-responders to treatment were those with worsening (increase in ≥2 steps) of inflammation in past 3 months on full-dose immunosuppressive therapy. P-gp expression of peripheral blood mononuclear cells of patients was assessed by flow cytometry with the dye Rhodamine-123, whose retention inside cells inversely correlates with P-gp expression. In non-responders receiving therapeutic vitrectomy for NIU, P-gp expression in CD4+ cells was compared between paired vitreous and blood samples.
Results :
Fourteen patients with non-infectious uveitis were recruited. Majority (n=8) were diagnosed Vogt-Koyanagi-Harada disease. These included 9 non-responders and 5 responders to IST. CD4+T cells showed significant difference in P-gp expression between responders and non-responders (Fig.1), as compared to CD8+ T-cells and CD14+ monocytes. Non-responders produced significantly higher pro-inflammatory cytokines (IFNγ, TNFα, IL-17 and GM-CSF), than responders, though no such difference was seen with IL-10. No difference in P-gp expression was found between Azathioprine and Methotrexate treated patients. Finally, significantly higher P-gp expression was found in CD4+ cells from vitreous of non-responders(n=3), compared to paired blood samples. In vitro cyclosporine treatment was found to inhibit P-gp expression and cytokine production, while increasing the regulatory T-cell transcription factor Foxp3.
Conclusions :
P-gp expression is significantly higher in CD4+ T-cells of non-responders to IST, and in vitreous CD4+ cells as compared to blood. Adjunctive cyclosporine therapy may decrease P-gp expression and allow improvement in treatment response to IST.
This abstract was presented at the 2019 ARVO Annual Meeting, held in Vancouver, Canada, April 28 - May 2, 2019.