1. Anti-IL-6 receptor monoclonal antibody inhibits leukocyte recruitment and promotes T-cell apoptosis in a murine model of Crohn's disease.
- Author
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Ito H, Hirotani T, Yamamoto M, Ogawa H, and Kishimoto T
- Subjects
- Animals, Antibodies, Monoclonal physiology, Apoptosis physiology, Cells, Cultured, Crohn Disease pathology, Cytokines analysis, Disease Models, Animal, Female, Immunoglobulin G pharmacology, Immunohistochemistry, In Situ Nick-End Labeling, Intercellular Adhesion Molecule-1 analysis, Intestinal Mucosa metabolism, Intestinal Mucosa pathology, Male, Mice, Mice, SCID, Nitric Oxide Synthase analysis, Nitric Oxide Synthase metabolism, Probability, Receptors, Interleukin-6 metabolism, Reference Values, Reverse Transcriptase Polymerase Chain Reaction methods, Sensitivity and Specificity, T-Lymphocytes drug effects, Vascular Cell Adhesion Molecule-1 analysis, Antibodies, Anti-Idiotypic pharmacology, Antibodies, Monoclonal drug effects, Apoptosis drug effects, Crohn Disease drug therapy, Receptors, Interleukin-6 drug effects, T-Lymphocytes physiology
- Abstract
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.
- Published
- 2002
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