title: Transient blockade of delta-like Notch ligands prevents allograft rejection mediated by cellular and humoral mechanisms in a mouse model of heart transplantation.
abstract: Rejection remains a major clinical challenge limiting allograft survival after solid organ transplantation. Both cellular and humoral immunity contribute to this complication, with increased recognition of Ab-mediated damage during acute and chronic rejection. Using a mouse model of MHC-mismatched heart transplantation, we report markedly protective effects of Notch inhibition, dampening both T cell and Ab-driven rejection. T cell-specific pan-Notch blockade prolonged heart allograft survival and decreased IFN-γ and IL-4 production by alloreactive T cells, especially when combined with depletion of recipient CD8(+) T cells. These effects were associated with decreased infiltration by conventional T cells and an increased proportion of regulatory T cells in the graft. Transient administration of neutralizing Abs specific for delta-like (Dll)1/4 Notch ligands in the peritransplant period led to prolonged acceptance of allogeneic hearts, with superior outcome over Notch inhibition only in T cells. Systemic Dll1/4 inhibition decreased T cell cytokines and graft infiltration, germinal center B cell and plasmablast numbers, as well as production of donor-specific alloantibodies and complement deposition in the transplanted hearts. Dll1 or Dll4 inhibition alone provided partial protection. Thus, pathogenic signals delivered by Dll1/4 Notch ligands early after transplantation promote organ rejection through several complementary mechanisms. Transient interruption of these signals represents an attractive new therapeutic strategy to enhance long-term allograft survival.
authors: Department of Surgery, University of Michigan, Ann Arbor, MI 48109;
authors: Sherri
authors: S
authors: Wood
authors: Department of Surgery, University of Michigan, Ann Arbor, MI 48109;
authors: Jiane
authors: J
authors: Feng
authors: Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109; Graduate Program in Cellular and Molecular Biology, University of Michigan, Ann Arbor, MI; Medical Scientist Training Program, University of Michigan, Ann Arbor, MI;
authors: Jooho
authors: J
authors: Chung
authors: Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109; Division of Hematology-Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI;
authors: Vedran
authors: V
authors: Radojcic
authors: Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109; Graduate Program in Immunology, University of Michigan, Ann Arbor, MI;
authors: Ashley R
authors: AR
authors: Sandy-Sloat
authors: Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109;
authors: Ann
authors: A
authors: Friedman
authors: Department of Discovery Oncology, Genentech Inc., South San Francisco, CA 94080;
authors: Amy
authors: A
authors: Shelton
authors: Department of Molecular Oncology, Genentech Inc., South San Francisco, CA 94080; and.
authors: Minhong
authors: M
authors: Yan
authors: Department of Discovery Oncology, Genentech Inc., South San Francisco, CA 94080;
authors: Christian W
authors: CW
authors: Siebel
authors: Department of Surgery, University of Michigan, Ann Arbor, MI 48109; kbishop@umich.edu imaillar@umich.edu.
authors: D Keith
authors: DK
authors: Bishop
authors: Life Sciences Institute, University of Michigan, Ann Arbor, MI 48109; Division of Hematology-Oncology, Department of Internal Medicine, University of Michigan, Ann Arbor, MI; Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, MI 48109 kbishop@umich.edu imaillar@umich.edu.
authors: Ivan
authors: I
authors: Maillard
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D057134:Antibodies, Neutralizing / Q000276:immunology* / Q000494:pharmacology; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D002135:Calcium-Binding Proteins; D005434:Flow Cytometry; D006084:Graft Rejection / Q000276:immunology* / Q000517:prevention & control; D006085:Graft Survival / Q000276:immunology; D016027:Heart Transplantation / Q000379:methods*; D007109:Immunity / Q000276:immunology*; D007111:Immunity, Cellular / Q000276:immunology; D056724:Immunity, Humoral / Q000276:immunology; D036341:Intercellular Signaling Peptides and Proteins / Q000276:immunology* / Q000378:metabolism; D007371:Interferon-gamma / Q000276:immunology / Q000378:metabolism; D015847:Interleukin-4 / Q000276:immunology / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000276:immunology* / Q000378:metabolism; D008565:Membrane Proteins / Q000276:immunology* / Q000378:metabolism; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D051880:Receptors, Notch / Q000037:antagonists & inhibitors / Q000276:immunology / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000276:immunology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D013997:Time Factors; D014184:Transplantation, Homologous
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D057134:Antibodies, Neutralizing; D002135:Calcium-Binding Proteins; C519665:DLL4 protein, mouse; C512925:Dlk1 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D051880:Receptors, Notch; D015847:Interleukin-4; D007371:Interferon-gamma