Altered peptide ligands inhibit arthritis induced by glucose-6-phosphate isomerase peptide

作者：Iwanami Keiichi; Matsumoto Isao^*; Yoshiga Yohei; Inoue Asuka; Kondo Yuya; Yamamoto Kayo; Tanaka Yoko; Minami Reiko; Hayashi Taichi; Goto Daisuke; Ito Satoshi; Nishimura Yasuharu; Sumida Takayuki

来源：Arthritis Research and Therapy, 2009, 11(6): R167.

DOI：10.1186/ar2854

Introduction Immunosuppressants, including anti-TNF alpha antibodies, have remarkable effects in rheumatoid arthritis; however, they increase infectious events. The present study was designed to examine the effects and immunological change of action of altered peptide ligands (APLs) on glucose-6-phosphate isomerase (GPI) peptide-induced arthritis.
Methods DBA/1 mice were immunized with hGPI(325-339), and cells of draining lymph node (DLN) were stimulated with hGPI(325-339) to investigate the T-cell receptor (TCR) repertoire of antigen-specific CD4( ) T cells by flow cytometry. Twenty types of APLs with one amino acid substitution at a TCR contact site of hGPI(325-339) were synthesized. CD4( ) T cells primed with human GPI and antigen-presenting cells were co-cultured with each APL and cytokine production was measured by ELISA to identify antagonistic APLs. Antagonistic APLs were co-immunized with hGPI(325-339) to investigate whether arthritis could be antigen-specifically inhibited by APL. After co-immunization, DLN cells were stimulated with hGPI(325-339) or APL to investigate Th17 and regulatory T-cell population by flow cytometry, and anti-mouse GPI antibodies were measured by ELISA.
Results Human GPI(325-339)-specific Th17 cells showed predominant usage of TCRV beta 8.1 8.2. Among the 20 synthesized APLs, four (APL 6; N329S, APL 7; N329T, APL 12; G332A, APL 13; G332V) significantly reduced IL-17 production by CD4( ) T cells in the presence of hGPI(325-339). Co-immunization with each antagonistic APL markedly prevented the development of arthritis, especially APL 13 (G332V). Although co-immunization with APL did not affect the population of Th17 and regulatory T cells, the titers of anti-mouse GPI antibodies in mice co-immunized with APL were significantly lower than in those without APL.
Conclusions We prepared antagonistic APLs that antigen-specifically inhibited the development of experimental arthritis. Understanding the inhibitory mechanisms of APLs may pave the way for the development of novel therapies for arthritis induced by autoimmune responses to ubiquitous antigens.

• 出版日期2009