An interleukin 12 p40-IgG2b fusion protein abrogates T cell mediated inflammation: anti-inflammatory activity in Crohn's disease and experimental colitis in vivo. (11th February 2004)

• Record Type: Journal Article
• Authors: Stallmach, A; Marth, T; Weiß, B; Wittig, B M; Hombach, A; Schmidt, C; Neurath, M; Zeitz, M; Zeuzem, S; Abken, H
• Is Part Of: Gut. Volume 53:(2004)Supplement 3
• Page Start: 339
• Page End: 345
• Publication Date: 2004-02-11
• Subjects: interleukin 12 -- fusion protein -- Crohn's disease -- inflammatory bowel disease; 5-ASA, 5-aminosalicylic acid -- CD, Crohn's disease -- TNBS, 2, 4, 6, -trinitrobenzene sulphonic acid -- LPMNC, lamina propria mononuclear cells -- PBMNC, peripheral blood mononuclear cells -- IL, interleukin -- IFN-γ, interferon γ -- mAb, monoclonal antibody -- PCR, polymerase chain reaction -- PBS, phosphate buffered saline -- PMA, phorbol myristate acetate -- PBL, peripheral blood lymphocytes -- TNF-α, tumour necrosis factor α; Gastroenterology -- Periodicals; 616.33
• DOI: 10.1136/gut.2003.020107
• Languages: English
• ISSNs: 0017-5749

Abstract

Abstract : Background and aims: Interleukin-12 (IL-12), a p35/p40 heterodimer, plays a pivotal role 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 an 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 an 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.