Lymphotoxin (LT) is a TNF family cytokine. Blocking of LTalpha(Α)1beta(Β)2–LTBreceptor (LTΒR) interactions prevents experimental colitis and other experimental
autoimmune disease in mice, suggesting a potential treatment principle of human inflammatory
bowel disease (IBD). Infection of mice with Citrobacter rodentium (C. r.) serves as an animal model for human infectious colitis induced by enteropathogen
E. coli (EPEC).
We studied the role of LTΑ1Β2–LTΒR signaling in C. r.–induced colitis. Methods: Mice with disrupted LTΑ1Β2–LTΒR interactions secondary to gene defects (-/-)(LTΑ-/-, LTΒ-/-, LTΒR-/-) or treatment
with antagonist LTΒR-IgG fusion protein (LTΒRIgG) were infected with C.r. Bodyweight, fecal excretion of C. r. and disease related mortality were monitored. Spleen and liver organ cultures of
mice assessed systemic infection. Intestinal inflammation and lymphoid architecture
were histologically recorded in the large intestine, mesenteric lymph nodes and spleen
of infected mice.
Inhibition of LTΑ1Β2–LTΒR interactions was associated with increased severity of C. r.-induced colitis. Infected LTΑ-/-, LTΒ-/- and LTΒR-/- mice died following C. r. infection whereas wild type mice survived and cleared the infection. There was more
disease related mortality and weight loss in LTΒRIgG-treated infected mice than in
control mice. Bacterial abscesses in the lamina propria of infected -/- and LTΒRIgG
treated mice were noted histologically. A higher burden of C. r. was detected in the
livers and spleens of infected -/- mice and LTΒRIgG treated mice. There was a fourfold
reduction of CD11c+ dendritic cells in the spleen of all gene deficient mice and LTΒRIgG treated mice
suggesting impaired bacterial dendritic cell function in these mice.
LTΑ1Β2-LTΒR interactions are critical for the immunity against C. r. in mice. Impaired anti-EPEC immunity may be anticipated in anti-LTΒR-directed therapy
of human IBD.
Key words
mucosal immunity lymphotoxin lymphoid microenvironment
