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Blood, 15 January 2008, Vol. 111, No. 2, pp. 705-714. Prepublished online as a Blood First Edition Paper on October 9, 2007; DOI 10.1182/blood-2007-05-087353. This Article Full Text Full Text (PDF) All Versions of this Article: blood-2007-05-087353v1 111/2/705    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 Teachey, D. T. Articles by Grupp, S. A. Search for Related Content PubMed PubMed Citation Articles by Teachey, D. T. Articles by Grupp, S. A. Related Collections Immunobiology Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  IMMUNOBIOLOGY Targeting Notch signaling in autoimmune and lymphoproliferative disease David T. Teachey1,2, Alix E. Seif1,2, Valerie I. Brown1, Marlo Bruno1, Ralph M. Bunte3, Yueh J. Chang1, John K. Choi4, Jonathan D. Fish1,2, Junior Hall1, Gregor S. Reid1, Theresa Ryan1, Cecilia Sheen1, Patrick Zweidler-McKay5, and Stephan A. Grupp1,4 Divisions of1 Oncology and 2 Hematology, Department of Pediatrics, Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine; 3 University Laboratory Animal Resources, University of Pennsylvania School of Medicine, Philadelphia; 4 Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine; and 5 Division of Pediatrics at University of Texas M. D. Anderson Cancer Center, Houston Patients with autoimmune lymphoproliferative syndrome (ALPS) and systemic lupus erythematosis (SLE) have T-cell dysregulation and produce abnormal, activated T lymphocytes and an atypical peripheral T-cell population, termed double negative T cells (DNTs). T-cell functions, including DNT transition in T-cell development and T-cell activation, are critically dependent on Notch signaling. We hypothesized that inhibiting Notch signaling would be effective in ALPS and SLE by reducing the production of abnormal DNTs and by blocking aberrant T-cell activation. We tested this hypothesis using murine models of ALPS and SLE. Mice were randomized to treatment with the notch pathway inhibitor (gamma-secretase inhibitor), N-S-phenyl-glycine-t-butyl ester (DAPT), or vehicle control. Response to treatment was assessed by measurement of DNTs in blood and lymphoid tissue, by monitoring lymph node and spleen size with ultrasound, by quantifying cytokines by bead-array, by ELISA for total IgG and anti–double-stranded DNA (dsDNA) specific antibodies, and by histopathologic assessment for nephritis. We found a profound and statistically significant decrease in all disease parameters, comparing DAPT-treated mice to controls. Using a novel dosing schema, we avoided the reported toxicities of gamma-secretase inhibitors. Inhibiting the Notch signaling pathway may thus present an effective, novel, and well-tolerated treatment for autoimmune and lymphoproliferative diseases. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: Taking ALPS down a Notch V. Koneti Rao Blood 2008 111: 477. [Full Text] [PDF] This article has been cited by other articles: P. R. Mertens, U. Raffetseder, and T. Rauen Notch receptors: a new target in glomerular diseases Nephrol. Dial. Transplant., May 25, 2008; (2008) gfn279v1. [Full Text] [PDF]

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