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
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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Proinflammatory functions of vascular endothelial growth factor in alloimmunity

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 intragraft 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.

Authors

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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Function of VEGF in human leukocyte recruitment. Saline, IgG, or anti–hu...
Function of VEGF in human leukocyte recruitment. Saline, IgG, or anti–human VEGF were received by huSCID mice bearing human skin transplants. (a–i) Skin grafts were harvested 14 days after humanization and infiltrates were identified by H&E staining (a–c), by immunostaining with anti–human CD3 (d–f), and by immunostaining with anti–human CD68 (g–i). Treatment of huSCID mice with anti–human VEGF inhibited both CD3+ T cell (f) and CD68+ monocyte macrophage (i) infiltration of skin. (j) Quantitative assessment of CD3+ T cell infiltrates was performed by calibrated grid counting at a magnification of ×400 in skin specimens harvested at either day 7 or day 14 following humanization. The mean CD3 count per calibrated field is illustrated in skins harvested from animals treated with saline (n = 7 at day 7; n = 10 at day 14), anti–human VEGF (n = 5 at day 7; n = 10 at day 14), or control IgG (n = 4 at day 14).