Vascular Endothelial Growth Factor Receptor Interactions and Allograft Rejection

描述(申请人提供)：这个项目是基于观察到血管内皮生长因子(VEGF)在同种异体移植物中过度表达，与缺血再灌注、体液免疫以及急性和慢性排斥反应有关。目前的研究表明，它是介导血管重塑的主要因素，特别是与慢性炎症相关。然而，血管内皮生长因子也有很强的促炎作用，与细胞介导的免疫炎症有关。这项研究的新颖性与最近的观察结果有关，即血管内皮生长因子受体(VEGFR)、KDR(VEGFR2)、Flt-1(VEGFR1)和神经粘连蛋白家族分子在效应细胞、记忆细胞和FOXP3High T调节细胞上表达。此外，我们正在进行的观察表明，血管内皮生长因子-KDR相互作用在调节T效应细胞内的运动和激活反应方面是有效的。然而，目前尚不清楚血管内皮生长因子是否可以与所有T细胞亚群相互作用，或者它是否在不同表达VEGFR的T细胞中介导不同的反应。在这份R01中，我们计划探讨血管内皮生长因子和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其在T效应细胞和T调节细胞上表达的共同神经毛刺素受体相互作用。由于VEGF被认为与3类信号素竞争与神经粘连蛋白的结合，这些观察结果提出了一个问题：VEGF结合是否会改变Sema3诱导的抑制性/调节性免疫反应。我们的假设是，移植物内的血管内皮生长因子与循环中表达VEGFR的T细胞相互作用，并且T细胞亚群上的单个VEGFR激发促进或抑制迁移和激活反应的信号。我们将在两个特定的目标中验证这一假说：1)确定血管内皮生长因子受体在T细胞亚群中的表达和功能，并评估血管内皮生长因子和3类信号素在T细胞趋化、激活和免疫调节反应中的相互作用；2)确定体内血管内皮生长因子-神经粘连蛋白-信号素相互作用在同种异体移植排斥反应生理模型中的作用。我们建议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，将体外发现转化为体内临床相关的模型。总而言之，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移植内血管内皮生长因子，可能是一种新的因子，协调移植体内循环中表达VEGFR的T效应细胞和T调节细胞之间的相互作用。 公共卫生相关性：器官移植是终末期器官衰竭患者的一种挽救生命的疗法，但所有移植最终都会因为一种称为慢性同种异体移植排斥反应的过程而失败。我们发现血管内皮细胞生长因子(VEGF)可以促进T细胞的募集和激活。在这项研究方案中，我们计划进行机制研究，以解决T细胞中血管内皮生长因子受体相互作用的分子基础，以及移植器官中过度表达的血管内皮生长因子如何导致慢性排斥反应。

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. PUBLIC HEALTH RELEVANCE: Organ transplantation is a life saving therapy for individuals with end stage organ failure, but all transplants eventually fail due to a process called chronic allograft rejection. We have identified that Vascular Endothelial Growth Factor (VEGF) facilitates the recruitment and activation of T cells. In this research proposal, we plan to perform mechanistic studies addressing questions about the molecular basis for VEGF receptor interactions in T cells, and how overexpressed VEGF within transplanted organs may result in chronic rejection.