Z Gastroenterol 2004; 42 - P078
DOI: 10.1055/s-2004-831532

Lymphotoxin beta controls immunity in experimental colitis by regulation of splenic dendritic cell homing

TW Spahn 1, C Maaser 2, A Lügering 2, J Heidemann 2, H Herbst 3, W Domschke 2, T Kucharzik 2
  • 1Medizinische Klinik und Poliklinik B, Westfälische Wilhelms Universität Münster
  • 2Medizinische Klinik und Poliklinik B, Westfälische Wilhelms-Universität Münster
  • 3Gerhard-Domagk-Institut für Pathologie des UK Münster

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