An interleukin 12 p40-lgG2b hjsion protein abrogates T cell mediated inflammation: anti-inflammatory activily in Crohn's disease and experimental colitis in vivo

Staumach, A.; Marth, T.; Weiß, B.; Wittig, B. M.; Hombach, A.; Schmidt, C.; Neurath, M.; Zeitz, M.; Zeuzem, S.; Abken, H.
March 2004
Gut;Mar2004, Vol. 53 Issue 3, p339
Academic Journal
Background and aims: Interleukin-12 (IL-12), a p35/p40 heterodimer, plays a pivotal rote in the immune response in Crohn's disease (CD). Since IL-12 p40 dimers act as IL-12 antagonists, we assayed p40 dimer proteins to modulate chronic intestinal inflammation. Methods: We generated a fusion protein consisting of the IL-12(p40) subunit fused to the constant region of IgG2b. IL-12(p40)-IgG2b was tested in a murine 2,4,6,-trinitrobenzene sulphonic acid (TNBS) colitis model and in lamina propria mononuclear cells (LPMNC) from patients with CD in vitro. Results: Dimeric IL-12(p40)-IgG2b fusion protein bound specifically to the IL-12 receptor. In concentrations <10-7 M, it acted as on IL-12 antagonist as it inhibited interferon γ (IFN-γ) secretion, suppressed proliferation, and increased apoptosis of LPMNC from patients with CD. However, in concentrations >10-6 M, IL-12(p40)-IgG2b increased IFN-γ secretion and lymphocyte proliferation thereby acting as on IL-12 agonist. In TNBS colitic mice, IL-12(p40)-IgG2b decreased mortality (10% v 68%), prevented body weight loss, reduced tumour necrosis factor α, and increased IL-10 secretion. Conclusions: The IL-12(p40)-IgG2b fusion protein has dichotomic properties as a specific IL-12 antagonist and selective repressor of mucosal inflammation at low concentration and as an IL-12 agonist at high concentration.


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