title: Targeting the Notch Pathway to Prevent Rejection.
abstract: Immune rejection is mediated by a complex interplay of cellular and humoral mechanisms. Current therapeutic strategies, which rely on global immunosuppression, can result in serious complications and are not completely effective. Notch signaling is a cell-to-cell communication pathway that plays an important role during T cell development and in the regulation of peripheral immune responses. Initial work, performed mainly through gain-of-function approaches, paradoxically identified Notch as an inducer of tolerance; however, recent studies using loss-of-function approaches in mouse models of transplant rejection and graft-versus-host disease have clarified an important role for Notch as a central mediator of T cell alloreactivity. Short-term inhibition of individual Notch ligands in the peritransplant period had long-lasting protective effects. In a vascularized heart allograft model, blockade of Delta-like Notch ligands dampened both cellular and humoral rejection. In this minireview, we summarize current knowledge about the role of Notch signaling during allograft rejection and provide an overarching mechanism through which Notch acts to promote T cell pathogenicity and allograft damage. We propose that targeting elements of the Notch pathway could provide a new therapeutic approach to prevent allograft rejection.
authors.affiliation: Graduate Program in Cellular and Molecular Biology, University of Michigan, Ann Arbor, MI.|Life Sciences Institute, University of Michigan, Ann Arbor, MI.
authors.forename: J
authors.initials: J
authors.lastname: Chung
authors.affiliation: Schuster Transplantation Research Center, Harvard Medical School, Boston, MA.|Renal Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.
authors.forename: L V
authors.initials: LV
authors.lastname: Riella
authors.affiliation: Life Sciences Institute, University of Michigan, Ann Arbor, MI. imaillar@umich.edu.|Division of Hematology-Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI. imaillar@umich.edu.|Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI. imaillar@umich.edu.
authors.forename: I
authors.initials: I
authors.lastname: Maillard
mesh_terms: D000818:Animals; D006084:Graft Rejection / Q000378:metabolism / Q000517:prevention & control*; D006801:Humans; D051880:Receptors, Notch / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D051880:Receptors, Notch
keywords: T cell biology; basic (laboratory) research/science; bone marrow/hematopoietic stem cell transplantation; graft-versus-host disease (GVHD); heart (allograft) function/dysfunction; heart transplantation/cardiology; immunosuppression/immune modulation; rejection: T cell mediated (TCMR); rejection: antibodymediated (ABMR); translational research/science