Document Detail


Blockade of individual Notch ligands and receptors controls graft-versus-host disease.
MedLine Citation:
PMID:  23454750     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Graft-versus-host disease (GVHD) is the main complication of allogeneic bone marrow transplantation. Current strategies to control GVHD rely on global immunosuppression. These strategies are incompletely effective and decrease the anticancer activity of the allogeneic graft. We previously identified Notch signaling in T cells as a new therapeutic target for preventing GVHD. Notch-deprived T cells showed markedly decreased production of inflammatory cytokines, but normal in vivo proliferation, increased accumulation of regulatory T cells, and preserved anticancer effects. Here, we report that γ-secretase inhibitors can block all Notch signals in alloreactive T cells, but lead to severe on-target intestinal toxicity. Using newly developed humanized antibodies and conditional genetic models, we demonstrate that Notch1/Notch2 receptors and the Notch ligands Delta-like1/4 mediate all the effects of Notch signaling in T cells during GVHD, with dominant roles for Notch1 and Delta-like4. Notch1 inhibition controlled GVHD, but led to treatment-limiting toxicity. In contrast, Delta-like1/4 inhibition blocked GVHD without limiting adverse effects while preserving substantial anticancer activity. Transient blockade in the peritransplant period provided durable protection. These findings open new perspectives for selective and safe targeting of individual Notch pathway components in GVHD and other T cell-mediated human disorders.
Authors:
Ivy T Tran; Ashley R Sandy; Alexis J Carulli; Christen Ebens; Jooho Chung; Gloria T Shan; Vedran Radojcic; Ann Friedman; Thomas Gridley; Amy Shelton; Pavan Reddy; Linda C Samuelson; Minhong Yan; Christian W Siebel; Ivan Maillard
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  The Journal of clinical investigation     Volume:  123     ISSN:  1558-8238     ISO Abbreviation:  J. Clin. Invest.     Publication Date:  2013 Apr 
Date Detail:
Created Date:  2013-05-09     Completed Date:  2013-05-20     Revised Date:  2014-05-29    
Medline Journal Info:
Nlm Unique ID:  7802877     Medline TA:  J Clin Invest     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1590-604     Citation Subset:  AIM; IM    
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MeSH Terms
Descriptor/Qualifier:
Amyloid Precursor Protein Secretases / antagonists & inhibitors
Animals
Antibodies / administration & dosage
Bone Marrow Transplantation
Cell Proliferation
Diarrhea / chemically induced
Dibenzazepines / administration & dosage,  adverse effects
Graft vs Host Disease / metabolism*,  prevention & control
Intercellular Signaling Peptides and Proteins / physiology
Interferon-gamma / metabolism
Interleukin-2 / metabolism
Intestines / drug effects,  physiopathology
Intracellular Signaling Peptides and Proteins / physiology
Membrane Proteins / physiology
Mice
Mice, Inbred BALB C
Mice, Inbred C57BL
Mice, Transgenic
Receptor, Notch1 / antagonists & inhibitors,  physiology*
Receptor, Notch2 / antagonists & inhibitors,  physiology*
Regeneration / drug effects
Signal Transduction
T-Lymphocytes / physiology
Transplantation, Homologous
Grant Support
ID/Acronym/Agency:
AI007413-17/AI/NIAID NIH HHS; F30 DK095517/DK/NIDDK NIH HHS; GM007315/GM/NIGMS NIH HHS; GM07863/GM/NIGMS NIH HHS; HD007505/HD/NICHD NIH HHS; HL007622-26/HL/NHLBI NIH HHS; P30-CA46592/CA/NCI NIH HHS; P50 CA093990/CA/NCI NIH HHS; R01 AI091627/AI/NIAID NIH HHS; R01-AI091627/AI/NIAID NIH HHS; T32 GM007315/GM/NIGMS NIH HHS
Chemical
Reg. No./Substance:
0/Antibodies; 0/DLL4 protein, mouse; 0/Dibenzazepines; 0/Dlk1 protein, mouse; 0/Intercellular Signaling Peptides and Proteins; 0/Interleukin-2; 0/Intracellular Signaling Peptides and Proteins; 0/Membrane Proteins; 0/Notch1 protein, mouse; 0/Notch2 protein, mouse; 0/Receptor, Notch1; 0/Receptor, Notch2; 0/dibenzazepine; 82115-62-6/Interferon-gamma; EC 3.4.-/Amyloid Precursor Protein Secretases
Comments/Corrections

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