Chronic murine colitis is dependent on the CD154/CD40 pathway and can be attenuated by anti-CD154 administration

Gastroenterology. 2000 Sep;119(3):715-23. doi: 10.1053/gast.2000.16485.


Background & aims: Experimental colitis in most animal models is caused by dysregulation of T lymphocytes that display a T helper 1 (Th1) phenotype. CD154 (CD40L/gp39), a member of the tumor necrosis factor (TNF) family, is up-regulated on T cells on activation and has been shown to play a key role in the induction of a Th1 response. We investigated whether chronic experimental colitis is dependent on the CD154/CD40 pathway and whether disease can be prevented by anti-CD154 antibody treatment.

Methods: Two models of chronic colitis were used: CD45Rb(hi) cell transfer into recombination activation gene-deficient (Rag(-/-)) mice and bone marrow transplant of tgepsilon26 animals. In both models, mice were reconstituted with cells from CD154-deficient animals. In another series of experiments, wild-type CD45Rb(hi) T cell-reconstituted recipients were treated with anti-CD154, either from the start of the experiment or after onset of disease.

Results: T cells deficient in CD154 induced a milder clinical disease, less weight loss, and fewer histologic signs of colitis than wild-type cells. The level of interleukin 12 in the serum of CD154-deficient T-cell recipients was 5-fold less than that of wild-type cell recipients. Nevertheless, no signs of deviation from a Th1 phenotype were observed. Treatment with anti-CD154 antibodies substantially impaired disease development, even when started after the onset of colitis.

Conclusions: The CD154/CD40 pathway plays a critical role in Th1-induced chronic experimental colitis. Blocking CD154, even after the onset of disease, ameliorates colitis but does not induce a T helper 2 (Th2) phenotype.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Animals
  • Antibodies / pharmacology*
  • CD40 Antigens / physiology*
  • CD40 Ligand
  • Chronic Disease
  • Colitis / immunology
  • Colitis / pathology
  • Colitis / physiopathology*
  • Colitis / prevention & control*
  • Membrane Glycoproteins / analysis
  • Membrane Glycoproteins / deficiency
  • Membrane Glycoproteins / immunology*
  • Membrane Glycoproteins / physiology*
  • Mice
  • Mice, Inbred Strains
  • T-Lymphocytes / immunology


  • Antibodies
  • CD40 Antigens
  • Membrane Glycoproteins
  • CD40 Ligand