Critical role of effector macrophages in mediating CD4-dependent alloimmune injury of transplanted liver parenchymal cells

Phillip H. Horne, Jason M. Zimmerer, Mason G. Fisher, Keri E. Lunsford, Gyongyi Nadasdy, Tibor Nadasdy, Nico Van Rooijen, Ginny L. Bumgardner

    Research output: Contribution to journalArticlepeer-review

    21 Scopus citations

    Abstract

    Despite the recognition that humoral rejection is an important cause of allograft injury, the mechanism of Ab-mediated injury to allograft parenchyma is not well understood. We used a well-characterized murine hepatocellular allograft model to determine the mechanism of Ab-mediated destruction of transplanted liver parenchymal cells. In this model, allogeneic hepatocytes are transplanted into CD8-deficient hosts to focus on CD4-dependent, alloantibody-mediated rejection. Host serum alloantibody levels correlated with in vivo allospecific cytotoxic activity in CD8 knockout hepatocyte rejector mice. Host macrophage depletion, but not CD4+ T cell, NK cell, neutrophil, or complement depletion, inhibited in vivo allocytotoxicity. Recipient macrophage deficiency delayed CD4-dependent hepatocyte rejection and inhibited in vivo allocytotoxicity without influencing alloantibody production. Furthermore, hepatocyte coincubation with alloantibody and macrophages resulted in Ab-dependent hepatocellular cytotoxicity in vitro. These studies are consistent with a paradigm of acute humoral rejection in which CD4+ T cell-dependent alloantibody production results in the targeting of transplanted allogeneic parenchymal cells for macrophage-mediated cytotoxic immune damage. Consequently, strategies to eliminate recipient macrophages during CD4-dependent rejection pathway may prolong allograft survival.

    Original languageEnglish (US)
    Pages (from-to)1224-1231
    Number of pages8
    JournalJournal of Immunology
    Volume181
    Issue number2
    DOIs
    StatePublished - Jul 15 2008

    ASJC Scopus subject areas

    • Immunology and Allergy
    • Immunology

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