title: Chronic murine colitis is dependent on the CD154/CD40 pathway and can be attenuated by anti-CD154 administration.
abstract: OBJECTIVE
  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.
authors.affiliation: Division of Immunology, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, USA.
authors.forename: Y P
authors.initials: YP
authors.lastname: De Jong
authors.forename: M
authors.initials: M
authors.lastname: Comiskey
authors.forename: S L
authors.initials: SL
authors.lastname: Kalled
authors.forename: E
authors.initials: E
authors.lastname: Mizoguchi
authors.forename: R A
authors.initials: RA
authors.lastname: Flavell
authors.forename: A K
authors.initials: AK
authors.lastname: Bhan
authors.forename: C
authors.initials: C
authors.lastname: Terhorst
mesh_terms: D000818:Animals; D000906:Antibodies / Q000494:pharmacology*; D019013:CD40 Antigens / Q000502:physiology*; D023201:CD40 Ligand; D002908:Chronic Disease; D003092:Colitis / Q000276:immunology / Q000473:pathology / Q000503:physiopathology* / Q000517:prevention & control*; D008562:Membrane Glycoproteins / Q000032:analysis / Q000172:deficiency / Q000276:immunology* / Q000502:physiology*; D051379:Mice; D008815:Mice, Inbred Strains; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: D000906:Antibodies; D019013:CD40 Antigens; D008562:Membrane Glycoproteins; D023201:CD40 Ligand