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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.
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Submitted May 16, 2007
Accepted September 23, 2007
Targeting Notch signaling in autoimmune and lymphoproliferative disease
David T Teachey*, Alix E Seif, Valerie I. Brown, Marlo Bruno, Ralph M Bunte, Yueh J Chang, John K Choi, Jonathan D Fish, Junior Hall, Gregor S Reid, Theresa Ryan, Cecilia Sheen, Patrick Zweidler-McKay, and Stephan A. Grupp
Division of Hematology, Department of Pediatrics, Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, PA, United States
Division of Oncology, Department of Pediatrics, Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, PA, United States
University Laboratory Animal Resources, University of Pennsylvania School of Medicine, Philadelphia, PA, United States
Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine, Philadelphia, PA, United States
Division of Pediatrics, UT MD Anderson Cancer Center, Houston, TX, United States
* Corresponding author; email: teacheyd{at}email.chop.edu.
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 function, 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), 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-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 control. 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.
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