Proinflammatory functions of vascular endothelial growth factor in alloimmunity

Marlies E.J. Reinders, Masayuki Sho, Atsushi Izawa, Ping Wang, Debabrata Mukhopadhyay, Kerith E. Koss, Christopher S. Geehan, Andrew D. Luster, Mohamed H. Sayegh, David M. Briscoe

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174 Scopus citations

Abstract

Vascular endothelial growth factor (VEGF), an established angiogenesis factor, is expressed in allografts undergoing rejection, but its function in the rejection process has not been defined. Here, we initially determined that VEGF is functional in the trafficking of human T cells into skin allografts in vivo in the humanized SCID mouse. In vitro, we found that VEGF enhanced endothelial cell expression of the chemokines monocyte chemoattractant protein 1 and IL-8, and in combination with IFN-γ synergistically induced endothelial cell production of the potent T cell chemoattractant IFN-inducible protein-10 (IP-10). Treatment of BALB/c (H-2d) recipients of fully MHC-mismatched C57BL/6 (H-2b) donor hearts with anti-VEGF markedly inhibited T cell infiltration of allografts and acute rejection. Anti-VEGF failed to inhibit T cell activation responses in vivo, but inhibited intra-graft expression of several endothelial cell adhesion molecules and chemokines, including IP-10. In addition, whereas VEGF expression was increased, neovascularization was not associated with acute rejection, and treatment of allograft recipients with the angiogenesis inhibitor endostatin failed to inhibit leukocyte infiltration of the grafts. Thus, VEGF appears to be functional in acute allograft rejection via its effects on leukocyte trafficking. Together, these observations provide mechanistic insight into the proinflammatory function of VEGF in immunity.

Original languageEnglish (US)
Pages (from-to)1655-1665
Number of pages11
JournalJournal of Clinical Investigation
Volume112
Issue number11
DOIs
StatePublished - Dec 2003

ASJC Scopus subject areas

  • Medicine(all)

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    Reinders, M. E. J., Sho, M., Izawa, A., Wang, P., Mukhopadhyay, D., Koss, K. E., Geehan, C. S., Luster, A. D., Sayegh, M. H., & Briscoe, D. M. (2003). Proinflammatory functions of vascular endothelial growth factor in alloimmunity. Journal of Clinical Investigation, 112(11), 1655-1665. https://doi.org/10.1172/JCI17712