Expression and function of inducible co-stimulator in patients with systemic lupus erythematosus: possible involvement in excessive interferon-gamma and anti-double-stranded DNA antibody production.
Inducible co-stimulator (ICOS) is the third member of the CD28/cytotoxic T-lymphocyte associated antigen-4 family and is involved in the proliferation and activation of T cells. A detailed functional analysis of ICOS on peripheral blood T cells from patients with systemic lupus erythematosus (SLE) has not yet been reported. In the present study we developed a fully human anti-human ICOS mAb (JTA009) with high avidity and investigated the immunopathological roles of ICOS in SLE. JTA009 exhibited higher avidity for ICOS than a previously reported mAb, namely SA12. Using JTA009, ICOS was detected in a substantial proportion of unstimulated peripheral blood T cells from both normal control individuals and patients with SLE. In CD4+CD45RO+ T cells from peripheral blood, the percentage of ICOS+ cells and mean fluorescence intensity with JTA009 were significantly higher in active SLE than in inactive SLE or in normal control individuals. JTA009 co-stimulated peripheral blood T cells in the presence of suboptimal concentrations of anti-CD3 mAb. Median values of [3H]thymidine incorporation were higher in SLE T cells with ICOS co-stimulation than in normal T cells, and the difference between inactive SLE patients and normal control individuals achieved statistical significance. ICOS co-stimulation significantly increased the production of IFN-gamma, IL-4 and IL-10 in both SLE and normal T cells. IFN-gamma in the culture supernatants of both active and inactive SLE T cells with ICOS co-stimulation was significantly higher than in normal control T cells. Finally, SLE T cells with ICOS co-stimulation selectively and significantly enhanced the production of IgG anti-double-stranded DNA antibodies by autologous B cells. These findings suggest that ICOS is involved in abnormal T cell activation in SLE, and that blockade of the interaction between ICOS and its receptor may have therapeutic value in the treatment of this intractable disease.
Institute of Rheumatology, Tokyo Women's Medical University, Tokyo, Japan.
Manabu
M
Kawamoto
Masayoshi
M
Harigai
Masako
M
Hara
Yasushi
Y
Kawaguchi
Katsunari
K
Tezuka
Michi
M
Tanaka
Tomoko
T
Sugiura
Yasuhiro
Y
Katsumata
Chikako
C
Fukasawa
Hisae
H
Ichida
Satomi
S
Higami
Naoyuki
N
Kamatani
D000911:Antibodies, Monoclonal; D001323:Autoantibodies / Q000097:blood*; D001402:B-Lymphocytes / Q000276:immunology; D018920:Coculture Techniques; D016207:Cytokines / Q000097:blood; D004247:DNA / Q000276:immunology*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood; D007371:Interferon-gamma / Q000097:blood*; D016753:Interleukin-10 / Q000097:blood; D007376:Interleukin-2 / Q000235:genetics / Q000502:physiology*; D015847:Interleukin-4 / Q000097:blood; D008180:Lupus Erythematosus, Systemic / Q000097:blood / Q000235:genetics / Q000276:immunology*; D008213:Lymphocyte Activation; D008297:Male; D012016:Reference Values; D013601:T-Lymphocytes / Q000276:immunology
D000911:Antibodies, Monoclonal; D001323:Autoantibodies; D016207:Cytokines; D007074:Immunoglobulin G; D007376:Interleukin-2; D016753:Interleukin-10; D015847:Interleukin-4; D007371:Interferon-gamma; D004247:DNA