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, Plays a Major Role in Sustaining the Chronic Phase of Colitis in IL-10-Deficient Mice1
*
DNAX Research Institute of Cellular and Molecular Biology, Palo Alto, CA 94304; and
Schering-Plough Research Institute, Lafayette, NJ 07848
IL-10-deficient (IL-10-/-) mice develop chronic
enterocolitis mediated by CD4+ Th1 cells producing IFN-
.
Because IL-12 can promote Th1 development and IFN- production, the
ability of neutralizing anti-IL-12 mAb to modulate colitis in
IL-10-/- mice was investigated. Anti-IL-12 mAb treatment
completely prevented disease development in young
IL-10-/- mice. Treatment of adult mice resulted in
significant amelioration of established disease accompanied by reduced
numbers of mesenteric lymph node and colonic CD4+ T cells
and of mesenteric lymph node T cells spontaneously producing IFN-.
In contrast, anti-IFN- mAb had minimal effect on disease
reversal, despite a significant preventative effect in young mice.
These findings suggested that IL-12 sustains colitis by supporting the
expansion of differentiated Th1 cells that mediate disease
independently of their IFN- production. This conclusion was
supported by the finding that anti-IL-12 mAb greatly diminished the
ability of a limited number of CD4+ T cells expressing high
levels of CD45RB from diseased IL-10-/- mice to expand
and cause colitis in recombination-activating gene-2-/-
recipients, while anti-IFN- mAb had no effect. Furthermore,
IL-12 could support pathogenic IL-10-/- T cells
stimulated in vitro in the absence of IL-2. While these studies show
that IL-12 plays an important role in sustaining activated Th1 cells
during the chronic phase of disease, the inability of anti-IL-12
mAb to abolish established colitis or completely prevent disease
transfer by Th1 cells suggests that additional factors contribute to
disease maintenance.
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