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Blood, 1 February 2007, Vol. 109, No. 3, pp. 1156-1164. Prepublished online as a Blood First Edition Paper on October 19, 2006; DOI 10.1182/blood-2006-04-019398. This Article Full Text Full Text (PDF) All Versions of this Article: blood-2006-04-019398v1 109/3/1156    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Wada, Y. Articles by Ono, M. Search for Related Content PubMed PubMed Citation Articles by Wada, Y. Articles by Ono, M. Related Collections Immunobiology Immunotherapy Chemokines, Cytokines, and Interleukins Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  IMMUNOBIOLOGY Selective abrogation of Th1 response by STA-5326, a potent IL-12/IL-23 inhibitor Yumiko Wada1, Rongzhen Lu1, Dan Zhou1, John Chu1, Teresa Przewloka1, Shijie Zhang1, Long Li1, Yaming Wu1, June Qin1, Vishwasenani Balasubramanyam1, James Barsoum1, and Mitsunori Ono2 1 Synta Pharmaceuticals Corp, Lexington, MA; and 2 Department of Pathology, Beth Israel Deaconness Medical Center, Harvard Medical School, Boston, MA The interleukin-12 (IL-12) cytokine induces the differentiation of naive T cells to the T helper cell type 1 (Th1) phenotype and is integral to the pathogenesis of Th1-mediated immunologic disorders. A more recently discovered IL-12 family member, IL-23, shares the p40 protein subunit with IL-12 and plays a critical role in the generation of effector memory T cells and IL-17–producing T cells. We introduce a novel compound, STA-5326, that down-regulates both IL-12 p35 and IL-12/IL-23 p40 at the transcriptional level, and inhibits the production of both IL-12 and IL-23 cytokines. Oral administration of STA-5326 led to a suppression of the Th1 but not Th2 immune response in mice. In vivo studies using a CD4+CD45Rbhigh T-cell transfer severe combined immunodeficiency (SCID) mouse inflammatory bowel disease model demonstrated that oral administration of STA-5326 markedly reduced inflammatory histopathologic changes in the colon. A striking decrease in interferon- (IFN-) production was observed in ex vivo culture of lamina propria cells harvested from animals treated with STA-5326, indicating a down-regulation of the Th1 response by STA-5326. These results suggest that STA-5326 has potential for use in the treatment of Th1-related autoimmune or immunologic disorders. STA-5326 currently is being evaluated in phase 2 clinical trials in patients with Crohn disease and rheumatoid arthritis. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: H. Okamoto, S. Momohara, G. G. Krueger, R. G. Langley, and N. Yeilding Interleukin-12/23 Monoclonal Antibody for Psoriasis N. Engl. J. Med., May 10, 2007; 356(19): 2003 - 2003. [Full Text] [PDF]

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