Therapeutic effects of antibodies to tumor necrosis factor-alpha, interleukin-6 and cytotoxic T-lymphocyte antigen 4 immunoglobulin in mice with glucose-6-phosphate isomerase induced arthritis.
BACKGROUND
Immunization with glucose-6-phosphate isomerase (GPI) induces severe arthritis in DBA/1 mice. The present study was designed to identify the cytokines and co-stimulatory molecules involved in the development of GPI-induced arthritis.


METHODS
Arthritis was induced in DBA/1 mice with 300 microg human recombinant GPI. CD4+ T cells and antigen-presenting cells from splenocytes of arthritic mice were cultured in the presence of GPI. Tumor necrosis factor (TNF)-alpha, IFN-gamma, IL-2, IL-4, IL-5, IL-6, IL-10, and IL-12 levels were assessed using cytometric bead array. Monoclonal antibodies to TNF-alpha, IFN-gamma, IL-12, CD40L, inducible co-stimulator (ICOS), and cytotoxic T-lymphocyte antigen 4 immunoglobulin (CTLA-4Ig) were used to block TNF-alpha and IFN-gamma production, examine clinical index in mice with GPI-induced arthritis, and determine anti-GPI antibody production.


RESULTS
Large amounts of TNF-alpha and IFN-gamma and small amounts of IL-2 and IL-6 were produced by splenocytes from mice with GPI-induced arthritis. Anti-TNF-alpha mAbs and CTLA-4Ig suppressed TNF-alpha production, whereas anti-IFN-gamma mAbs, anti-IL-12 mAbs, and CTLA-4 Ig inhibited IFN-gamma production. A single injection of anti-TNF-alpha and anti-IL-6 mAbs and two injections of CTLA-4Ig reduced the severity of arthritis in mice, whereas injections of anti-IFN-gamma and anti-IL-12 mAbs tended to exacerbate arthritis. Therapeutic efficacy tended to correlate with reduction in anti-GPI antibodies.


CONCLUSIONS
TNF-alpha and IL-6 play an important role in GPI-induced arthritis, whereas IFN-gamma appears to function as a regulator of arthritis. Because the therapeutic effects of the tested molecules used in this study are similar to those in patients with rheumatoid arthritis, GPI-induced arthritis appears to be a suitable tool with which to examine the effect of various therapies on rheumatoid arthritis.
Division of Clinical Immunology, Major of Advanced Biomedical Applications, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tennodai, Tsukuba 305-8575, Japan. ismatsu@md.tsukuba.ac.jp
Isao
I
Matsumoto
Hua
H
Zhang
Takanori
T
Yasukochi
Keiichi
K
Iwanami
Yoko
Y
Tanaka
Asuka
A
Inoue
Daisuke
D
Goto
Satoshi
S
Ito
Akito
A
Tsutsumi
Takayuki
T
Sumida
D000069594:Abatacept; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D001172:Arthritis, Rheumatoid / Q000139:chemically induced / Q000201:enzymology / Q000276:immunology* / Q000628:therapy*; D005956:Glucose-6-Phosphate Isomerase / Q000633:toxicity*; D006801:Humans; D018796:Immunoconjugates / Q000378:metabolism*; D015850:Interleukin-6 / Q000276:immunology*; D008297:Male; D051379:Mice; D008811:Mice, Inbred DBA; D014409:Tumor Necrosis Factor-alpha / Q000037:antagonists & inhibitors / Q000276:immunology*; D000093242:Interleukin-6 Inhibitors
D000069594:Abatacept; D000911:Antibodies, Monoclonal; D005956:Glucose-6-Phosphate Isomerase; D018796:Immunoconjugates; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; D000093242:Interleukin-6 Inhibitors