Vascular Endothelial Growth Factor Receptor Interactions and Allograft Rejection

描述（由申请人提供）：该项目基于对血管内皮生长因子（VEGF）在同种异体移植物中过表达与缺血再灌注、体液免疫和急性和慢性排斥反应相关的观察。目前的研究表明，它是介导血管重构的主要因素，特别是与慢性炎症有关。然而，VEGF在细胞介导的免疫炎症中也具有强大的促炎作用。该研究方案的新颖性与最近观察到的VEGF受体（VEGFR） KDR （VEGFR2）、Flt-1 （VEGFR1）和neuropilin家族分子在效应细胞、记忆细胞和foxp3高T调节细胞群体中表达有关。此外，我们正在进行的观察表明，VEGF-KDR相互作用可以有效地介导T效应细胞内的运动和激活反应。然而，目前尚不清楚VEGF是否可以与所有的T细胞亚群相互作用，或者它是否在不同表达VEGF的T细胞中介导不同的反应。在本R01中，我们计划探讨VEGF和3类信号素之间的相互作用，以及这些分子如何在同种免疫反应中与它们在T效应细胞和T调节细胞上表达的常见神经肽受体相互作用。由于VEGF被认为与3类信号蛋白竞争与神经肽结合，这些观察结果提出了VEGF结合是否可能改变sema3诱导的抑制/调节免疫反应的问题。我们的假设是，植入体内的VEGF与循环中表达vegfr的T细胞相互作用，并且T细胞亚群上的单个vegfr引发促进或抑制迁移和激活反应的信号。我们将在两个特定目标中验证这一假设：1)确定vegfr在T细胞亚群中的表达和功能，并评估VEGF与3类信号素之间的相互作用对T细胞趋化、激活和免疫调节反应的影响；2)确定同种异体移植排斥生理模型中VEGF-neuropilin-信号素在体内相互作用的影响。我们提出的研究解决了新的和临床相关的问题，我们的方法提供了将体外研究结果转化为体内临床相关模型的凝聚力。总的来说，这一研究领域的意义和临床意义在于，传统上被认为只是作为血管生成因子的局部植入VEGF，可能是协调移植物内循环表达VEGF的T效应细胞和T调节细胞之间相互作用的新因子。

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.