Synergistic effect on the attenuation of collagen induced arthritis in tumor necrosis factor receptor I (TNFRI) and interleukin 6 double knockout mice.
OBJECTIVE
To evaluate any additive effect on attenuation of collagen induced arthritis (CIA) in tumor necrosis factor receptor I (TNFRI) and interleukin 6 (IL-6) double knockout (DKO) mice.


METHODS
CIA was induced in wild-type (Wt), TNFRI knockout (TNFRIKO), IL-6 knockout (IL-6KO), and DKO mice. Comparative studies were performed among these different mouse genotypes observing clinical (incidence, arthritis score), histological, radiologic, and immunological aspects.


RESULTS
More than 90% of the Wt, TNFRIKO, and IL-6KO mice developed definite CIA, while only 20% of the DKO mice did so. Severity of arthritis, indicated by the arthritis score, was significantly reduced in both the TNFRIKO and IL-6KO mice compared with the Wt mice. Moreover, the severity of arthritis in the DKO mice was significantly reduced compared with each single KO mouse (by arthritis scores; DKO vs TNFRIKO, IL-6KO mice, p < 0.05). In addition, histological and radiologic changes were also significantly reduced in the DKO mice compared with each single KO mouse (by histological and radiologic scores; DKO vs TNFRIKO, IL-6KO mice, p < 0.05 and p < 0.01 respectively). In immunological studies, serum anti-type II collagen (anti-CII) antibody concentrations were significantly decreased in the DKO mice compared with each single KO mouse (DKO vs TNFRIKO, IL-6KO mice, p < 0.01).


CONCLUSIONS
Simultaneous blockade of TNFRI and IL-6 showed synergistic rather than additive effects on the attenuation of CIA. Combinations of anti-TNF-a and anti-IL-6 therapy may provide clinical benefits for treatment of rheumatoid arthritis compared with therapy against each single cytokine.
Yamaguchi
Norihiko
N
Department of Molecular Medicine, Osaka University Medical School, Japan.
Ohshima
Shiro
S
Umeshita-Sasai
Mitsuko
M
Nishioka
Katsuhiro
K
Kobayashi
Hideyuki
H
Mima
Toru
T
Kishimoto
Tadamitsu
T
Saeki
Yukihiko
Y
D000818:Animals; D015703:Antigens, CD / Q000235:genetics*; D001169:Arthritis, Experimental / Q000453:epidemiology / Q000473:pathology / Q000503:physiopathology*; D003094:Collagen / Q000276:immunology; D007074:Immunoglobulin G / Q000097:blood; D015994:Incidence; D015850:Interleukin-6 / Q000235:genetics*; D051379:Mice; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics*; D047888:Receptors, Tumor Necrosis Factor, Type I; D012720:Severity of Illness Index
D015703:Antigens, CD; D007074:Immunoglobulin G; D015850:Interleukin-6; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I; D003094:Collagen