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HMPL-004 (Andrographis paniculata extract) Prevents Development of Murine Colitis by Inhibiting T-cell Proliferation and TH1/TH17 Responses

Michelsen, Kathrin S. PhD*; Wong, Michelle H. MD*; Ko, Brian BS*; Thomas, Lisa S. BS*; Dhall, Deepti MD; Targan, Stephan R. MD*

doi: 10.1002/ibd.22983
Original Basic Science Articles

Background: Extracts of the plant Andrographis paniculata have been used to treat inflammatory diseases in Asian countries. A recent double-blind, placebo-controlled trial of HMPL-004 (A. paniculata extract) has demonstrated its safety and effectiveness for induction of clinical response, remission, and mucosal healing in patients with mild to moderate ulcerative colitis (UC). We aimed to determine if HMPL-004 could prevent the development of T-cell-dependent murine colitis and to define its in vivo mechanism(s) of action.

Methods: CD4+CD45RBhigh T cells were transferred into Rag1−/− mice and gavaged daily with HMPL-004 or methyl cellulose (MC). Severity of colitis was evaluated by weight loss, histology, and cytokine expression.

Results: Mice treated with MC developed colitis within 4–7 weeks, as evaluated by weight loss, and severe intestinal inflammation. HMPL-004-treated mice did not lose weight and displayed only very mild intestinal inflammation. Tumor necrosis factor alpha (TNF-α), interleukin (IL)-1β, interferon-gamma (IFN-γ), and IL-22 expression were significantly decreased in HMPL-004-treated mice. We observed higher percentages of naïve CD4+ T cells in the lamina propria of HMPL-004-treated mice. At early timepoints HMPL-004-treated mice have significantly reduced splenic cell counts, reduced CD4+, and IL-17+, and IFN-γ+ T cells. Furthermore, HMPL-004 inhibited the proliferation of CD4+ T cells and differentiation into TH1/TH17 cells in vitro.

Conclusions: HMPL-004 inhibits the development of chronic colitis by affecting early T-cell proliferation, differentiation, and TH1/TH17 responses in a T-cell-driven model of colitis, presenting a unique mechanism of action. Our data suggest that HMPL-004 could be an attractive herbal therapeutic for inflammatory bowel disease.

Article first published online 21 December 2012

*F. Widjaja Foundation Inflammatory Bowel & Immunobiology Research Institute

Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, California.

Reprints: Stephan R. Targan, MD, F. Widjaja Foundation Inflammatory Bowel & Immunobiology Research Institute, Cedars-Sinai Medical Center, 8700 Beverly Blvd., Suite D4063, Los Angeles CA 90048 (e-mail: targans@cshs.org).

Supplemental digital content is available for this article. Direct URL citations appear in the printed text and are provided in the HTML and PDF versions of this article on the journal's Web site.

Supported by Hutchison MediPharma Ltd. (Shanghai, China).

(Inflamm Bowel Dis 2012;xx:xxx–xxx)

Received February 24, 2012

Accepted March 17, 2012

© Crohn's & Colitis Foundation of America, Inc.
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