VASCULAR ENDOTHELIAL GROWTH FACTOR IN ALLOIMMUNITY

描述（由申请人提供）： 同种异体移植排斥反应是一个复杂的多细胞过程，依赖于获得性免疫，需要成熟的CD 4 + T细胞、B细胞和巨噬细胞。然而，活化的、先前活化的和记忆性T细胞以及效应细胞必须与移植物内皮相互作用以介导排斥反应。事实上，越来越多的证据支持移植物内皮细胞在同种免疫反应中的多种重要作用。血管内皮生长因子（VEGF）是一种公认的最有效的血管生成因子，其活性包括内皮细胞存活、增殖和迁移。此外，VEGF通过增加内皮细胞通透性、诱导内皮细胞粘附分子的表达以及通过其作为单核细胞趋化因子的能力而作为促炎细胞因子。此外，据报道VEGF在急性和慢性同种异体移植排斥反应中表达，并与急性和慢性同种异体移植排斥反应相关。然而，没有研究评估其在同种异体移植排斥反应中的作用或作用机制。我们假设VEGF是同种异体移植排斥反应中的促炎细胞因子，通过其调节内皮细胞活化反应的能力。我们的初步研究表明，VEGF增强内皮细胞趋化因子的生产单独和与促炎细胞因子的组合。特别地，我们已经发现VEGF与IFN-γ的组合协同诱导T细胞趋化因子IP-10的表达，该趋化因子IP-10已知在排斥反应中具有功能意义。我们在最初的研究中也发现，VEGF对于同种异体移植物中同种异体反应性T细胞的募集具有功能。在这项研究计划中，我们将首次确定VEGF在同种免疫中的作用。我们建议将我们的机制研究的重点放在后VEGF受体信号介导的趋化因子的生产和VEGF对NF-κ B和STAT家族的转录因子的激活的有效的T细胞趋化因子IP-10的相关性的影响。其次，我们计划研究VEGF在体外募集同种异体反应性T细胞的功能机制，第三，我们将确定这些机制是否在体内同种异体移植排斥反应中具有重要意义。这些研究的结果应该产生有用的信息，为未来发展的新的治疗策略，也应该为确定VEGF作为一个新的目标在同种异体移植排斥反应提供了基础。

DESCRIPTION (provided by applicant): 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.