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*
Laboratory of Experimental Immunology,
Department of Pathology,
Laboratory of Experimental Transplantation, and
§
Department of Gastroenterology, University Hospital Gasthuisberg, Leuven, Belgium;
¶
Laboratory of Immunobiology, Rega Institute, University of Leuven, Leuven, Belgium; and
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Tanox Pharma, Amsterdam, The Netherlands
Increased expression of CD40 and CD40 ligand (CD40L or CD154) has
been found in inflamed mucosa of human inflammatory bowel disease
(IBD), and interactions between these molecules seem to be involved in
local cytokine production by macrophages. However, the precise role of
CD40 signaling in the pathogenesis of IBD is still poorly understood.
The aim of the present study was to investigate the in vivo relevance
of CD40 signaling in experimental colitis in SCID mice reconstituted
with syngeneic CD45RBhighCD4+ T cells. The
results demonstrated that CD40+ and CD40L+
cells as well as their mRNA levels were significantly increased in
inflamed mucosa. Administration of anti-CD40L neutralizing mAb over
an 8-wk period starting immediately after
CD45RBhighCD4+ T cell reconstitution completely
prevented symptoms of wasting disease. Intestinal mucosal inflammation
was effectively prevented, as revealed by abrogated leukocyte
infiltration and decreased CD54 expression and strongly diminished mRNA
levels of the proinflammatory cytokines IFN-
, TNF, and IL-12. When
colitic SCID mice were treated with anti-CD40L starting at 5 wk
after T cell transfer up to 8 wk, this delayed treatment still led to
significant clinical and histological improvement and down-regulated
proinflammatory cytokine secretion. These data suggest that the
CD40-CD40L interactions are essential for the Th1 inflammatory
responses in the bowel in this experimental model of colitis. Blockade
of CD40 signaling may be beneficial to human
IBD.
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