Combination treatment with fingolimod and a pathogenic antigen prevents relapse of glucose-6-phosphate isomerase peptide-induced arthritis.
BACKGROUND
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
GPI325-339-induced arthritis mice were treated for 5 days with FTY720 (1.0 mg/kg, p.o.) alone, GPI325-339 (10 μg/mouse, i.v.) alone, or with the FTY720 plus GPI325-339 combination. In some experiments, mice were resensitized with GPI325-339.


RESULTS
Following resensitization with GPI325-339, combination-treated mice exhibited neither severe relapse nor elevated lymphocyte infiltration in joints. Neither anti-human nor mouse GPI325-339 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 GPI325-339 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.


CONCLUSIONS
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.
Faculty of Pharmaceutical Sciences, Department of Pathological Biochemistry Setsunan University Osaka Japan.
Yuya
Y
Yoshida
Department of Experimental Immunology Immunology Frontier Research Center Osaka University Osaka Japan.
Norihisa
N
Mikami
Faculty of Pharmaceutical Sciences, Department of Pathological Biochemistry Setsunan University Osaka Japan.
Yuki
Y
Matsushima
Faculty of Pharmaceutical Sciences, Department of Pathological Biochemistry Setsunan University Osaka Japan.
Mai
M
Miyawaki
Faculty of Pharmaceutical Sciences, Department of Pathological Biochemistry Setsunan University Osaka Japan.
Hiroki
H
Endo
Faculty of Pharmaceutical Sciences, Department of Pathological Biochemistry Setsunan University Osaka Japan.
Rie
R
Banno
Faculty of Pharmaceutical Sciences, Department of Pathological Biochemistry Setsunan University Osaka Japan.
Takumi
T
Tsuji
Research Institute for Production and Development Kyoto Japan.
Tetsuro
T
Fujita
Faculty of Pharmaceutical Sciences, Department of Pathological BiochemistrySetsunan UniversityOsakaJapan; Research Institute for Production and DevelopmentKyotoJapan.
Takeyuki
T
Kohno
FTY720; immune tolerance; rheumatoid arthritis