Therapeutic strategy for rheumatoid arthritis by induction of myeloid-derived suppressor cells with high suppressive potential

Abstract

Combination treatment using fingolimod (FTY720), an immunomodulator, and a pathogenic antigen prevents the progression of glucose-6-phosphate isomerase (GPI)_325-339-induced arthritis. In this study, we focused on myeloid-derived suppressor cells (MDSCs; CD11b⁺Gr-1⁺ cells) and investigated the effects of the combination treatment on these cells. DBA/1J mice with GPI_325-339-induced arthritis were treated using FTY720 and/or GPI_325-339 for five days. The expanded CD11b⁺Gr-1⁺ cell population and its inhibitory potential were examined. The percentage of CD369⁺CD11b⁺Gr-1⁺ cells effectively increased in the combination-treated mice. The inhibitory potential of CD369⁺CD11b⁺Gr-1⁺ cells was higher than that of cells not expressing CD369. Among bone marrow cells, the expression of CD369 in CD11b⁺Gr-1⁺ cells increased following stimulation with granulocyte-macrophage colony-stimulating factor, and the expression of CD11c increased accordingly. The increased CD11c expression indicated a decrease in the potential to suppress T cell proliferation based on the results of the suppression assay. The percentage of CD11c^–CD369⁺ cells in CD11b⁺Gr-1⁺ cells that were induced by the combination treatment also increased, and these cells tended to have a higher capacity to inhibit T cell proliferation. In conclusion, the combination treatment using FTY720 and the pathogenic antigen effectively induces MDSC, which demonstrates a high potential for suppressing T cell proliferation in the lymph nodes, thereby establishing an immune-tolerant state.