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 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.
Davidson
N J
NJ
DNAX Research Institute of Cellular and Molecular Biology, Palo Alto, CA 94304, USA. davidson@dnax.org
Hudak
S A
SA
Lesley
R E
RE
Menon
S
S
Leach
M W
MW
Rennick
D M
DM
D019264:Adoptive Transfer; D000375:Aging / Q000235:genetics / Q000276:immunology; D000818:Animals; D000831:Animals, Newborn / Q000235:genetics / Q000254:growth & development / Q000276:immunology; D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D002908:Chronic Disease; D003092:Colitis / Q000209:etiology* / Q000235:genetics / Q000276:immunology* / Q000517:prevention & control; D004268:DNA-Binding Proteins / Q000235:genetics; D004359:Drug Therapy, Combination; D007274:Injections, Intraperitoneal; D007371:Interferon-gamma / Q000502:physiology*; D016753:Interleukin-10 / Q000172:deficiency / Q000235:genetics / Q000627:therapeutic use; D018664:Interleukin-12 / Q000276:immunology / Q000502:physiology*; D007958:Leukocyte Count; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D016176:T-Lymphocyte Subsets / Q000276:immunology / Q000637:transplantation
D000911:Antibodies, Monoclonal; D004268:DNA-Binding Proteins; C499308:Rag2 protein, mouse; C064655:V(D)J recombination activating protein 2; D016753:Interleukin-10; D018664:Interleukin-12; D007371:Interferon-gamma