IL-12, but not IFN-gamma, plays a major role in sustaining the chronic phase of colitis in IL-10-deficient mice

• Published in: The Journal of immunology (1950) Vol. 161; no. 6; pp. 3143 - 3149
• Main Authors: Davidson, N J, Hudak, S A, Lesley, R E, Menon, S, Leach, M W, Rennick, D M
• Format: Journal Article
• Language: English
• Published: United States 15-09-1998
• Subjects: Adoptive Transfer; Aging - genetics; Aging - immunology; Animals; Animals, Newborn - genetics; Animals, Newborn - growth & development; Animals, Newborn - immunology; Antibodies, Monoclonal - therapeutic use; Chronic Disease; Colitis - etiology; Colitis - genetics; Colitis - immunology; Colitis - prevention & control; DNA-Binding Proteins - genetics; Drug Therapy, Combination; Injections, Intraperitoneal; Interferon-gamma - physiology; Interleukin-10 - deficiency; Interleukin-10 - genetics; Interleukin-10 - therapeutic use; Interleukin-12 - immunology; Interleukin-12 - physiology; Leukocyte Count; Mice; Mice, Inbred Strains; Mice, Knockout; T-Lymphocyte Subsets - immunology; T-Lymphocyte Subsets - transplantation
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.161.6.3143

IL-10-deficient (IL-10(-/-)) mice develop chronic enterocolitis mediated 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 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-gamma. In contrast, anti-IFN-gamma 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-gamma 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-gamma 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 Thl cells suggests that additional factors contribute to disease maintenance.