IL-12, BUT NOT IFN-GAMMA, PLAYS A MAJOR ROLE IN SUSTAINING THE CHRONIC PHASE OF COLITIS IN IL-10-DEFICIENT MICE

IL-10-deficient (IL-10(-/-)) mice develop chronic enterocolitis mediat ed by CD4(+) Th1 cells producing IFN-gamma. Because IL-12 can promote Th1 development and IFN-gamma 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 significan t amelioration of established disease accompanied by reduced numbers o f mesenteric lymph node and colonic CD4(+) T cells and of mesenteric l ymph node T cells spontaneously producing IFN-gamma. In contrast, anti -IFN-gamma mAb had minimal effect on disease reversal, despite a signi ficant preventative effect in young mice. These findings suggested tha t IL-12 sustains colitis by supporting the expansion of differentiated Th1 cells that mediate disease independently of their IFN-gamma produ ction. This conclusion was supported by the finding that anti-IL-12 mA b greatly diminished the ability of a limited number df CD4(+) T cells expressing high levels of CD45RB from diseased IL-10(-/-) mice to exp and and cause colitis in recombination-activating gene-2(-/-) recipien ts, while anti-IFN-gamma mAb had no effect. Furthermore, IL-12 could s upport pathogenic IL-10(-/-) T cells stimulated in vitro in the absenc e 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 co mpletely prevent disease transfer by Th1 cells suggests that additiona l factors contribute to disease maintenance.