title: Blockade of individual Notch ligands and receptors controls graft-versus-host disease.
abstract: 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: Life Sciences Institute, University of Michigan, Ann Arbor, Michigan 48109, USA.
authors: Ivy T
authors: IT
authors: Tran
authors: Ashley R
authors: AR
authors: Sandy
authors: Alexis J
authors: AJ
authors: Carulli
authors: Christen
authors: C
authors: Ebens
authors: Jooho
authors: J
authors: Chung
authors: Gloria T
authors: GT
authors: Shan
authors: Vedran
authors: V
authors: Radojcic
authors: Ann
authors: A
authors: Friedman
authors: Thomas
authors: T
authors: Gridley
authors: Amy
authors: A
authors: Shelton
authors: Pavan
authors: P
authors: Reddy
authors: Linda C
authors: LC
authors: Samuelson
authors: Minhong
authors: M
authors: Yan
authors: Christian W
authors: CW
authors: Siebel
authors: Ivan
authors: I
authors: Maillard
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D053829:Amyloid Precursor Protein Secretases / Q000037:antagonists & inhibitors; D000818:Animals; D000906:Antibodies / Q000008:administration & dosage; D016026:Bone Marrow Transplantation; D002135:Calcium-Binding Proteins; D049109:Cell Proliferation; D003967:Diarrhea / Q000139:chemically induced; D003984:Dibenzazepines / Q000008:administration & dosage / Q000009:adverse effects; D006086:Graft vs Host Disease / Q000378:metabolism* / Q000517:prevention & control; D036341:Intercellular Signaling Peptides and Proteins / Q000502:physiology; D007371:Interferon-gamma / Q000378:metabolism; D007376:Interleukin-2 / Q000378:metabolism; D007422:Intestines / Q000187:drug effects / Q000503:physiopathology; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology; D008565:Membrane Proteins / Q000502:physiology; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D051881:Receptor, Notch1 / Q000037:antagonists & inhibitors / Q000502:physiology*; D051883:Receptor, Notch2 / Q000037:antagonists & inhibitors / Q000502:physiology*; D012038:Regeneration / Q000187:drug effects; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000502:physiology; D014184:Transplantation, Homologous
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000906:Antibodies; D002135:Calcium-Binding Proteins; C519665:DLL4 protein, mouse; D003984:Dibenzazepines; C512925:Dlk1 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D007376:Interleukin-2; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; C497762:Notch1 protein, mouse; C497765:Notch2 protein, mouse; D051881:Receptor, Notch1; D051883:Receptor, Notch2; D007371:Interferon-gamma; D053829:Amyloid Precursor Protein Secretases; C527817:dibenzazepine