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.
Matsumoto
Isao
I
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
Zhang
Hua
H
Yasukochi
Takanori
T
Iwanami
Keiichi
K
Tanaka
Yoko
Y
Inoue
Asuka
A
Goto
Daisuke
D
Ito
Satoshi
S
Tsutsumi
Akito
A
Sumida
Takayuki
T
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