Anti-IL-6 receptor monoclonal antibody inhibits leukocyte recruitment and promotes T-cell apoptosis in a murine model of Crohn's disease

J Gastroenterol. 2002 Nov;37 Suppl 14:56-61. doi: 10.1007/BF03326415.

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.

Publication types

  • Comparative Study

MeSH terms

  • Animals
  • Antibodies, Anti-Idiotypic / pharmacology*
  • Antibodies, Monoclonal / drug effects*
  • Antibodies, Monoclonal / physiology
  • Apoptosis / drug effects*
  • Apoptosis / physiology
  • Cells, Cultured
  • Crohn Disease / drug therapy*
  • 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 / drug effects*
  • Receptors, Interleukin-6 / metabolism
  • Reference Values
  • Reverse Transcriptase Polymerase Chain Reaction / methods
  • Sensitivity and Specificity
  • T-Lymphocytes / drug effects
  • T-Lymphocytes / physiology*
  • Vascular Cell Adhesion Molecule-1 / analysis

Substances

  • Antibodies, Anti-Idiotypic
  • Antibodies, Monoclonal
  • Cytokines
  • Immunoglobulin G
  • Receptors, Interleukin-6
  • Vascular Cell Adhesion Molecule-1
  • Intercellular Adhesion Molecule-1
  • Nitric Oxide Synthase