Combination treatment with fingolimod and a pathogenic antigen prevents relapse of glucose‐6‐phosphate isomerase peptide‐induced arthritis

Combination treatment with fingolimod (FTY720) plus pathogenic antigen is thought to prevent glucose‐6‐phosphate isomerase (GPI) 325‐339 ‐induced arthritis progression by effective induction of immune tolerance. Here, we examined the efficacy of this combination treatment on remission maintenance. Methods GPI 325‐339 ‐induced arthritis mice were treated for 5 days with FTY720 (1.0 mg/kg, p.o .) alone, GPI 325–339  (10 μg/mouse, i.v .) alone, or with the FTY720 plus GPI 325‐339 combination. In some experiments, mice were resensitized with GPI 325‐339 . Results Following resensitization with GPI 325‐339 , combination‐treated mice exhibited neither severe relapse nor elevated lymphocyte infiltration in joints. Neither anti‐human nor mouse GPI 325‐339 antibody levels were correlated with clinical symptoms. This suggests that combination treatment prevents relapse following resensitization via regulation of pathogenic antigen‐specific T cells. The proportion of regulatory T (Treg) cells in inguinal lymph nodes was increased post treatment in the FTY720 alone and FTY720 plus GPI 325‐339 groups. In contrast, the proportion of glucocorticoid‐induced tumor necrosis factor receptor‐family‐related gene/protein (GITR) + non‐Treg cells was increased only in combination‐treated mice. Furthermore, GITR + non‐Treg cells, which were induced by the combination treatment in vivo , possess suppressive activity and high ability to produce interleukin (IL)‐10. Conclusion GITR + non‐Treg cells might play a key role in relapse prevention following resensitization. Thus, this combination treatment might establish immune tolerance by induction of GITR + non‐Treg cells.