Research article
Altered peptide ligands inhibit arthritis induced by glucose-6-phosphate isomerase peptide
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* Corresponding author: Isao Matsumoto ismatsu@md.tsukuba.ac.jp
1 Department of Clinical Immunology, Doctoral Program in Clinical Science, Graduate School of Comprehensive Human Science, University of Tsukuba, 1-1-1 Tennoudai, Tsukuba 305-8575, Japan
2 PRESTO, Japan Science and Technology Agency, 4-1-8 Honcho Kawaguchi, Saitama 332-0012, Japan
3 Department of Immunogenetics, Graduate School of Medical Sciences, Kumamoto University, 2-39-1 Kurokami, Kumamoto 860-8556, Japan
Arthritis Research & Therapy 2009, 11:R167 doi:10.1186/ar2854
Published: 9 November 2009Abstract
Introduction
Immunosuppressants, including anti-TNFα 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 hGPI325-339, and cells of draining lymph node (DLN) were stimulated with hGPI325-339 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 hGPI325-339 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 hGPI325-339 to investigate whether arthritis could be antigen-specifically inhibited by APL. After co-immunization, DLN cells were stimulated with hGPI325-339 or APL to investigate Th17 and regulatory T-cell population by flow cytometry, and anti-mouse GPI antibodies were measured by ELISA.
Results
Human GPI325-339-specific Th17 cells showed predominant usage of TCRVβ8.1 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 hGPI325-339. 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.