Allograft rejection is a complex multicellular process that depends on acquired immunity and requires mature CD4+ T cells, B cells and macrophages. However, activated, previously activated and memory T cells, as well as effector cells, must interact with the graft endothelium in order to mediate rejection. Indeed, increasing evidence supports diverse and important roles for the graft endothelium in alloimmune responses. Vascular Endothelial Growth Factor (VEGF) is an established and most potent angiogenesis factor whose activities include endothelial cell survival, proliferation and migration. In addition, VEGF acts as a proinflammatory cytokine by increasing endothelial cell permeability, inducing the expression of endothelial cell adhesion molecules and via its ability as a monocyte chemoattractant. Furthermore, VEGF has been reported to be expressed in, and to be associated with, acute and chronic allograft rejection. However, no study has evaluated its role or mechanism of action of VEGF in allograft rejection. We hypothesize that VEGF is a proinflammatory cytokine in allografi rejection via its ability to regulate endothelial cell activation responses. Our preliminary studies demonstrate that VEGF augments endothelial cell chemokine production alone and in combination with proinflammatory cytokines. In particular, we have found that VEGF in combination with IFN-gamma synergistically induces the expression of the T cell chemoattractant chemokine IP-10 known to be of functional significance in rejection. We have also found in initial studies that VEGF is functional for the recruitment of alloreactive T cells into allografts. In this research proposal, for the first time we will establish a role for VEGF in alloimmunity. We propose to focus our mechanistic studies on post VEGF receptor signals mediating chemokine production and the effect of VEGF on the NF-kB and STAT family of transcription factors of relevance for the activation of the potent T cell chemoattractant IP-10. Second, we plan to investigate the mechanism of function of VEGF for the recruitment of alloreactive T cells in vitro, and third we will determine if these mechanisms are of importance in allograft rejection in vivo. The results of these studies should yield useful information for the future development of novel therapeutic strategies, and should also provide the foundation for the identification of VEGF as a novel target in allograft rejection.
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