Functional Mechanism(s) of the Inhibition of Disease Progression by Combination Treatment with Fingolimod plus Pathogenic Antigen in a Glucose-6-phosphate Isomerase Peptide-Induced Arthritis Mouse Model.

We previously reported that combination treatment with fingolimod (FTY720) plus antigenic peptide of glucose-6-phosphate isomerase (residues 325-339) (GPI(325-339)) from the onset of symptoms significantly inhibited disease progression in a mouse model of GPI(325-339)-induced arthritis. In this study, we investigated the mechanism(s) involved. The model mice were treated from arthritis onset with FTY720 alone, GPI(325-339) alone, or the combination of FTY720 plus GPI(325-339). At the end of treatment, inguinal lymph nodes (LNs) were excised and examined histologically and in flow cytometry. Levels of apoptotic cells, programmed death-l-expressing CD4(+)forkhead box P3(-) nonregulatory T cells (non-Tregs), and cytotoxic T-lymphocyte antigen 4-expressing non-Tregs in inguinal LNs were markedly increased in the combination treatment group mice. Regulatory T cells (Tregs) were also increased. These results indicate that combination treatment with FTY720 plus GPI(325-339) inhibits the progression of arthritis by inducing clonal deletion and anergy of pathogenic T cells and also by immune suppression via Tregs.