title: Targeting Notch signaling in autoimmune and lymphoproliferative disease.
abstract: 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.
authors.affiliation: Department of Pediatrics, Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine 19104, USA. teacheyd@email.chop.edu
authors.forename: David T
authors.initials: DT
authors.lastname: Teachey
authors.forename: Alix E
authors.initials: AE
authors.lastname: Seif
authors.forename: Valerie I
authors.initials: VI
authors.lastname: Brown
authors.forename: Marlo
authors.initials: M
authors.lastname: Bruno
authors.forename: Ralph M
authors.initials: RM
authors.lastname: Bunte
authors.forename: Yueh J
authors.initials: YJ
authors.lastname: Chang
authors.forename: John K
authors.initials: JK
authors.lastname: Choi
authors.forename: Jonathan D
authors.initials: JD
authors.lastname: Fish
authors.forename: Junior
authors.initials: J
authors.lastname: Hall
authors.forename: Gregor S
authors.initials: GS
authors.lastname: Reid
authors.forename: Theresa
authors.initials: T
authors.lastname: Ryan
authors.forename: Cecilia
authors.initials: C
authors.lastname: Sheen
authors.forename: Patrick
authors.initials: P
authors.lastname: Zweidler-McKay
authors.forename: Stephan A
authors.initials: SA
authors.lastname: Grupp
mesh_terms: D000818:Animals; D000974:Antibodies, Antinuclear / Q000097:blood / Q000276:immunology; D004151:Dipeptides / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood / Q000276:immunology; D008180:Lupus Erythematosus, Systemic / Q000097:blood / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000276:immunology; D008198:Lymph Nodes / Q000000981:diagnostic imaging / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D008232:Lymphoproliferative Disorders / Q000097:blood / Q000000981:diagnostic imaging / Q000188:drug therapy* / Q000276:immunology; D051379:Mice; D008808:Mice, Inbred CBA; D019463:Mice, Inbred MRL lpr; D009393:Nephritis / Q000097:blood / Q000000981:diagnostic imaging / Q000188:drug therapy / Q000276:immunology; D011897:Random Allocation; D051880:Receptors, Notch / Q000037:antagonists & inhibitors* / Q000276:immunology; D015398:Signal Transduction / Q000187:drug effects* / Q000276:immunology; D013154:Spleen / Q000000981:diagnostic imaging / Q000276:immunology / Q000378:metabolism; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D014463:Ultrasonography
chemical_list: D000974:Antibodies, Antinuclear; D004151:Dipeptides; D004791:Enzyme Inhibitors; D007074:Immunoglobulin G; C419410:N-(N-(3,5-difluorophenacetyl)alanyl)phenylglycine tert-butyl ester; D051880:Receptors, Notch