Proinflammatory functions of vascular endothelial growth factor in alloimmunity
Marlies E.J. Reinders, … , Mohamed H. Sayegh, David M. Briscoe
Marlies E.J. Reinders, … , Mohamed H. Sayegh, David M. Briscoe
Published December 1, 2003
Citation Information: J Clin Invest. 2003;112(11):1655-1665. https://doi.org/10.1172/JCI17712.
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Categories: Article Transplantation

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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Figure 6

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Function of VEGF in alloimmune T cell activation and allograft rejection...
Function of VEGF in alloimmune T cell activation and allograft rejection. (a) Anti–human VEGF or anti–murine VEGF antiserum was added into the human or the mouse MLR, respectively. Proliferation was assessed by [3H]thymidine incorporation for the last 18 hours of coculture. (b) The production of IFN-γ and IL-2 was assessed by ELISA in coculture supernatants from a human MLR. As illustrated, blockade of VEGF had no effect on proliferation or cytokine production in the MLR. Bars indicate the mean ± 1 SD for triplicate wells. Data are representative of three experiments with similar results. S, stimulators alone; R, responders alone. (c) Frequency of IFN-γ-producing cells in murine recipients of cardiac transplants as assessed by ELISPOT. Illust production of IFN-γ from a syngeneic, an untreated, and an anti-VEGF-treated animal. Representative of three such experiments performed in triplicate.