Antibody to human leukocyte antigen triggers endothelial exocytosis

Munekazu Yamakuchi, Nancy C. Kirkiles-Smith, Marcella Ferlito, Scott J. Cameron, Clare Bao, Karen Fox-Talbot, Barbara A. Wasowska, William M. Baldwin, Jordan S. Pober, Charles J. Lowenstein

Research output: Contribution to journalArticle

Abstract

Although antibodies to HLA play a role in the pathogenesis of diseases processes such as rejection of transplanted organs, the precise mechanisms by which antibodies cause tissue injury are not completely understood. We hypothesized that antibodies to host tissues cause inflammation in part by activating endothelial exocytosis of granules that contain prothrombotic mediators such as von Willebrand Factor (VWF) and proinflammatory mediators such as P-selectin. To test this hypothesis, we treated human endothelial cells with murine monoclonal antibody W6/32 to HLA class I and then measured exocytosis by the release of VWF and the externalization of P-selectin. Antibody to MLA activates endothelial exocytosis in a dose-dependent manner over time. The biologically active complement split product, C5a, adds a slight but significant increase to antibody induction of exocytosis. Antibody to HLA alone or with C5a did not damage the cells. Cross-linking of HLA appears to play a role in the ability of antibody to activate exocytosis, because the W6/32 monovalent Fab fragment did not activate VWF release, but the bivalent F(ab′)2 was effective in triggering exocytosis. To explore the in vivo effects of antibody upon graft injury, we infused W6/32 F(ab′)2 antibody to human HLA into severe combined immunodeficient/beige mice that had been transplanted with human skin grafts. Antibody to HLA activated exocytosis and inflammation in human skin grafts. Our data show that antibody to host antigens can activate human endothelial cell exocytosis and leukocyte trafficking. By triggering vascular inflammation, antibody activation of exocytosis may play a role in transplant rejection.

Original languageEnglish (US)
Pages (from-to)1301-1306
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume104
Issue number4
DOIs
StatePublished - Jan 23 2007

Keywords

  • Nitric oxide
  • Rejection
  • Transplant
  • Vasculopathy
  • Weibel-Palade body

ASJC Scopus subject areas

  • General

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