Gastroenterology

Gastroenterology

Volume 132, Issue 7, June 2007, Pages 2359-2370
Gastroenterology

Basic–alimentary tract
Monoclonal Anti–Interleukin 23 Reverses Active Colitis in a T Cell–Mediated Model in Mice

https://doi.org/10.1053/j.gastro.2007.03.104Get rights and content

Background & Aims: Interleukin (IL)-23 supports a distinct lineage of T cells producing IL-17 (Th17) that can mediate chronic inflammation. This study was performed to define the role of IL-23 and Th17 cells in chronic colitis in mice. Methods: Colitis was induced by transfer of a cecal bacterial antigen–specific C3H/HeJBir (C3Bir) CD4+ T-cell line to C3H/HeSnJ SCID mice. Cytokines were measured by flow cytometry, enzyme-linked immunosorbent assay, and real-time polymerase chain reaction. Monoclonal anti–IL-23p19 was administered at the same time as or 4 weeks after pathogenic CD4 T-cell transfer. A histopathology colitis score was assessed in a blinded fashion. Results: The pathogenic C3Bir CD4+ T-cell line contained more cells producing IL-17 than those producing interferon-γ and these were distinct subsets; after adoptive transfer to SCID recipients, Th17 cells were predominant in the lamina propria of mice with colitis. Bacteria-reactive CD4+ Th1 and Th17 lines were generated. The Th17 cells induced marked inflammation in a dose-dependent manner. Even at a dose as low as 104 cells/mouse, Th17 cells induced more severe disease than Th1 cells did at 106 cells/mouse. Monoclonal anti–IL-23p19 prevented and treated active colitis, with down-regulation of a broad array of inflammatory cytokines and chemokines in the colon. Anti–IL-23p19 induced apoptosis in colitogenic Th17 cells in vitro and in vivo. Conclusions: Bacterial-reactive CD4+ Th17 cells are potent effector cells in chronic colitis. Inhibition of IL-23p19 was effective in both prevention and treatment of active colitis. IL-23 is an attractive therapeutic target for inflammatory bowel disease.

Section snippets

Mice

C3H/HeJBir, C3H/HeJ, and C3H/HeSnJ-Pkrdcscid/Pkrdcscid (C3H.SCID) mice were obtained from The Jackson Laboratory (Bar Harbor, ME) and housed in the University of Alabama animal facility. All studies were approved by the Institutional Animal Care and Use Committee of the University of Alabama at Birmingham.

Reagents and Materials

Reagents and materials were purchased from the following sources. RPMI 1640, fetal calf serum, 2-mercaptoethanol, HEPES, l-glutamine, and sodium pyruvate were purchased from Life Technologies

Enhanced Expression of IL-12, IL-23, and Related Cytokines in Inflamed Colon

To address the potential role of IL-23 and related cytokines in the induction of colitis by CBA-specific CD4+ T cells, we studied the expression of multiple genes in colonic tissues of recipient C3H.SCID mice using real-time quantitative PCR. A total of 1 × 106 cells of the Bir14 CBA-specific CD4+ T-cell line were adoptively transferred into C3H.SCID mice. Anti-CD3 polyclonally activated CD4+ T cells were transferred into a group of C3H.SCID mice as a negative control. Eight weeks after

Discussion

IL-23 is a member of a family of heterodimeric cytokines that includes IL-12 and IL-27. Both IL-12 and IL-23 are produced by dendritic cells and share the IL-12 p40 subunit. Both cytokines likely play a role in host defense at mucosal surfaces, but their exact role is unknown. Uptake of translocated commensal bacteria by murine intestinal dendritic cells increases the expression of IL-23 but not IL-12p70.21 The function of such IL-23–producing dendritic cells in normal immune homeostasis is

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    Supported by grants PO1 DK044240, PO1 DK071176, and DK064400 from the National Institutes of Health.

    1

    C.O.E., Y.C., C.T.W., and T.R.S. have no conflict of interest to disclose.

    2

    T.K.M., R.B.F., and R.A.K. are employed by Schering-Plough Biopharma.

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