Vascular Endothelial Growth Factor Receptor Interactions and Allograft Rejection

描述（由申请人提供）：本项目基于血管内皮生长因子（VEGF）在同种异体移植物中过表达与缺血-再灌注、体液免疫和急性及慢性排斥反应相关的观察结果。目前的范式表明，它作为一个主导因素介导血管重塑，特别是与慢性炎症。然而，VEGF也具有与细胞介导的免疫炎症相关的强效促炎作用。这项研究提案的新奇与最近的观察结果有关，即VEGF受体（VEGFR）KDR（VEGFR 2），Flt-1（VEGFR 1）和神经纤毛蛋白家族分子在效应细胞，记忆细胞和FOXP 3 high T调节细胞群体上表达。此外，我们正在进行的观察表明，VEGF-KDR相互作用是有效的，以介导T效应细胞内的运动和激活反应。然而，目前尚不清楚VEGF是否可以与所有T细胞亚群相互作用，或者它是否在不同的表达VEGF的T细胞中介导不同的反应。在这个R 01中，我们计划质疑VEGF和3类信号蛋白之间的相互作用，以及这些分子如何在同种免疫反应中与T效应细胞和T调节细胞上表达的共同神经纤毛蛋白受体相互作用。由于VEGF被认为与3类脑信号蛋白竞争结合神经纤毛蛋白，这些观察结果提出了VEGF结合是否可能改变Sema 3诱导的抑制/调节免疫应答的问题。我们的假设是移植物内VEGF与循环中表达VEGF的T细胞相互作用，并且T细胞亚群上的单个VEGF引起促进或抑制迁移和活化反应的信号。我们将在两个特定的目标中测试这一假设，其中我们将1）确定VEGF在T细胞亚群中的表达和功能，并评估VEGF和3类脑信号蛋白之间对于T细胞趋化性、活化和免疫调节应答的相互作用，以及2）确定VEGF-神经纤毛蛋白-脑信号蛋白相互作用在同种异体移植排斥的生理模型中的体内作用。我们提出的研究解决了新的和临床相关的问题，我们的方法提供了凝聚力，将体外发现转化为临床相关的体内模型。总的来说，这一领域的研究的意义和临床相关性是，局部移植物内VEGF，这是传统上被认为是简单地作为一种血管生成因子，可能是一种新的因素，协调之间的相互作用循环VEGF表达T效应和T调节细胞内的移植物。

DESCRIPTION (provided by applicant): This project is based on the observation that Vascular Endothelial Growth Factor (VEGF) is overexpressed within allografts in association with ischemia-reperfusion, humoral immunity and acute and chronic rejection. Current paradigms suggest that it functions as a dominant factor mediating vascular remodeling, especially in association with chronic inflammation. However, VEGF also has potent proinflammatory effects in association with cell-mediated immune inflammation. The novelty of this research proposal relates to recent observations that the VEGF receptors (VEGFR) KDR (VEGFR2), Flt-1 (VEGFR1) and neuropilin family molecules are expressed on populations of effector, memory and FOXP3high T regulatory cells. Further, our ongoing observations indicate that VEGF-KDR interactions are potent to mediate motility and activation responses within T effector cells. Nevertheless, it is not known if VEGF may interact with all T cell subsets, or whether it mediates different responses in different VEGFR-expressing T cells. In this R01, we plan to question the interplay between VEGF and Class 3 semaphorins, and how these molecules interact with their common neuropilin receptors expressed on T effector and T regulatory cells in the alloimmune response. Since VEGF is thought to compete with class 3 semaphorins for binding to the neuropilins, these observations beg the question whether VEGF binding may alter Sema3-inducible inhibitory/regulatory immune responses. Our hypothesis is that intragraft VEGF interacts with circulating VEGFR-expressing T cells, and that individual VEGFRs on T cell subsets elicit signals that either promote or suppress migratory and activation responses. We will test this hypothesis in two specific aims in which we will 1), determine the expression and function of VEGFRs in T cell subsets, and evaluate the interplay between VEGF and class 3 semaphorins for T cell chemotaxis, activation and immunoregulatory responses, and 2), determine the effect of VEGF-neuropilin-semaphorin interactions in vivo in physiological models of allograft rejection. Our proposed studies address novel and clinically relevant questions and our approach provides for cohesiveness to translate in vitro findings into clinically relevant models in vivo. Collectively, the implications and clinical relevance of this area of investigation is that local intragraft VEGF, which is traditionally thought to serve simply as an angiogenesis factor, may be a novel factor that coordinates interactions among circulating VEGFR-expressing T effector and T regulatory cells within the graft.