Anti-IL-6 receptor monoclonal antibody inhibits leukocyte recruitment and promotes T-cell apoptosis in a murine model of Crohn's disease.
BACKGROUND
To assess the contribution of IL-6 signaling to the physiopathology of Crohn's disease, we introduced anti-IL-6 receptor monoclonal antibody to a murine colitis model.


METHODS
Colitis was induced in C.B-17-scid mice to which were transferred CD45RBhigh CD4+ T cells from Balb/c mice. Anti-IL-6 receptor monoclonal antibody or rat IgG was given intraperitoneally after T-cell transfer, followed by weekly injection. Vascular adhesion molecules and inducible nitric oxide synthase were visualized by immunostaining. Cytokine expression was determined by RT-PCR, and apoptotic cells were determined by the TUNEL method.


RESULTS
Mice treated with anti-IL-6 receptor monoclonal antibody showed normal growth while controls lost weight. Colitis was improved histologically with reduced infiltration of LFA-1+ monocytes/macrophages and VLA-4+ T cells. ICAM-1 and VCAM-1 expression in the colonic vascular endothelium was markedly suppressed by the treatment, whereas no significant difference was seen in MAdCAM-1. IFN-gamma, TNF-alpha, and IL-1beta mRNAs were markedly reduced, but no difference was observed in the expression of IL-4, IL-10, and TGF-beta. Inducible nitric oxide synthase was upregulated in the mucosa of colitic mice and downregulated in the treated mice. Apoptotic cells were very sparse despite massive CD4+ T-cell infiltration in colitic mice, whereas increased apoptosis was seen in the treated mice with an apparently reduced number of T cells.


CONCLUSIONS
Anti-IL-6 receptor monoclonal antibody abrogated murine colitis. It effectively blocked the expression of adhesion molecules, thereby blocking leukocyte recruitment, and increased T-cell apoptosis. These results strongly suggest the therapeutic potential of anti-IL-6 receptor monoclonal antibody for human Crohn's disease.
Ito
Hiroaki
H
Osaka University Graduate School of Medicine, Department of Molecular Medicine, 2-2 Yamada-oka, Suita 565-0871, Japan.
Hirotani
Tomonori
T
Yamamoto
Mitsunari
M
Ogawa
Hiroyuki
H
Kishimoto
Tadamitsu
T
D000818:Animals; D000888:Antibodies, Anti-Idiotypic / Q000494:pharmacology*; D000911:Antibodies, Monoclonal / Q000187:drug effects* / Q000502:physiology; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D002478:Cells, Cultured; D003424:Crohn Disease / Q000188:drug therapy* / Q000473:pathology; D016207:Cytokines / Q000032:analysis; D004195:Disease Models, Animal; D005260:Female; D007074:Immunoglobulin G / Q000494:pharmacology; D007150:Immunohistochemistry; D020287:In Situ Nick-End Labeling; D018799:Intercellular Adhesion Molecule-1 / Q000032:analysis; D007413:Intestinal Mucosa / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D016513:Mice, SCID; D019001:Nitric Oxide Synthase / Q000032:analysis / Q000378:metabolism; D011336:Probability; D019947:Receptors, Interleukin-6 / Q000187:drug effects* / Q000378:metabolism; D012016:Reference Values; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D012680:Sensitivity and Specificity; D013601:T-Lymphocytes / Q000187:drug effects / Q000502:physiology*; D019010:Vascular Cell Adhesion Molecule-1 / Q000032:analysis
D000888:Antibodies, Anti-Idiotypic; D000911:Antibodies, Monoclonal; D016207:Cytokines; D007074:Immunoglobulin G; D019947:Receptors, Interleukin-6; D019010:Vascular Cell Adhesion Molecule-1; D018799:Intercellular Adhesion Molecule-1; D019001:Nitric Oxide Synthase