Chronic murine colitis is dependent on the CD154/CD40 pathway and can be attenuated by anti-CD154 administration.
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.
De Jong
Y P
YP
Division of Immunology, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02215, USA.
Comiskey
M
M
Kalled
S L
SL
Mizoguchi
E
E
Flavell
R A
RA
Bhan
A K
AK
Terhorst
C
C
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
D000906:Antibodies; D019013:CD40 Antigens; D008562:Membrane Glycoproteins; D023201:CD40 Ligand