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.
Copyright © 2015 by The American Association of Immunologists, Inc.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing
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Animals
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Antibodies, Neutralizing / immunology*
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Antibodies, Neutralizing / pharmacology
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CD8-Positive T-Lymphocytes / drug effects
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CD8-Positive T-Lymphocytes / immunology
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CD8-Positive T-Lymphocytes / metabolism
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Calcium-Binding Proteins
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Flow Cytometry
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Graft Rejection / immunology*
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Graft Rejection / prevention & control
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Graft Survival / immunology
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Heart Transplantation / methods*
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Immunity / immunology*
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Immunity, Cellular / immunology
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Immunity, Humoral / immunology
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Intercellular Signaling Peptides and Proteins / immunology*
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Intercellular Signaling Peptides and Proteins / metabolism
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Interferon-gamma / immunology
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Interferon-gamma / metabolism
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Interleukin-4 / immunology
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Interleukin-4 / metabolism
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Intracellular Signaling Peptides and Proteins / immunology*
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Intracellular Signaling Peptides and Proteins / metabolism
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Membrane Proteins / immunology*
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Membrane Proteins / metabolism
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Mice, Inbred BALB C
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Mice, Inbred C57BL
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Mice, Transgenic
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Receptors, Notch / antagonists & inhibitors
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Receptors, Notch / immunology
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Receptors, Notch / metabolism
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Signal Transduction / drug effects
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Signal Transduction / immunology
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T-Lymphocytes / drug effects
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T-Lymphocytes / immunology
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T-Lymphocytes / metabolism
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Time Factors
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Transplantation, Homologous
Substances
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Adaptor Proteins, Signal Transducing
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Antibodies, Neutralizing
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Calcium-Binding Proteins
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DLL4 protein, mouse
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Dlk1 protein, mouse
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Intercellular Signaling Peptides and Proteins
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Intracellular Signaling Peptides and Proteins
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Membrane Proteins
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Receptors, Notch
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Interleukin-4
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Interferon-gamma