VASCULAR ENDOTHELIAL GROWTH FACTOR IN ALLOIMMUNITY

同种免疫中的血管内皮生长因子

• 批准号: 7248054
• 负责人: David M. Briscoe
• 金额: $ 38.4万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-08-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7248054
• 关键词: Acute; Adhesions; Alloantigen; Allogenic; Allografting; Angiogenic Factor; Animals; Antibodies; Area; Attention; B-Lymphocytes; Biological; Biology; Blocking Antibodies; Blood; Blood Vessels; CCL2 gene; CD4 Positive T Lymphocytes; CXCL10 gene; Cell Adhesion Molecules; Cell Line; Cell Survival; Cells; Cellular biology; Chemotactic Factors; Chronic; Complex; Condition; Data; Development; Effector Cell; Endothelial Cells; Endothelium; Event; Family; Foundations; Future; Genetic Polymorphism; Genetic Transcription; Healed; Heart Transplantation; Human; In Vitro; Infiltration; Inflammation; Inflammatory; Interferon Type II; Interferons; Knockout Mice; Laboratories; Lead; Length; Leukocyte Trafficking; Leukocytes; Lymphocyte; MHC Class I Genes; Mediating; Modeling; Molecular; Mononuclear; Multicellular Process; Mus; NF-kappa B; Numbers; Pathway interactions; Patients; Pattern; Permeability; Phase; Positioning Attribute; Process; Production; Property; Publishing; Reaction; Reagent; Receptor Signaling; Regulation; Reporting; Research Personnel; Research Proposals; Role; Signal Transduction; Signaling Molecule; Site; Stimulus; T memory cell; T-Cell Activation; T-Lymphocyte; Testing; Time; Tissues; Transactivation; Transplant Recipients; Transplantation; VEGFA gene; Vascular Endothelial Growth Factor Receptor; Vascular Endothelial Growth Factors; acquired immunity; base; cell motility; chemokine; chemokine receptor; cytokine; experience; healing; in vivo; isoimmunity; knockout animal; macrophage; migration; monocyte; neovascularization; novel; novel therapeutics; promoter; receptor; response; tool; transcription factor

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.

描述（由申请人提供）： 同种异体移植排斥是一个复杂的多细胞过程，取决于获得的免疫力，需要成熟的CD4+ T细胞，B细胞和巨噬细胞。然而，已激活的，先前激活的和记忆T细胞以及效应细胞必须与移植内皮相互作用，以介导排斥反应。实际上，越来越多的证据支持移植物内皮在同种免疫反应中的各种重要作用。血管内皮生长因子（VEGF）是一种已建立，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通过增加内皮细胞的渗透性，诱导内皮细胞粘附分子的表达以及作为单核细胞趋化剂的能力来充当促炎细胞因子。此外，据报道，VEGF在急性和慢性同种异体移植排斥中被表达并与之相关。但是，尚无研究评估其VEGF在同种异体移植排斥反应中的作用或作用机理。我们假设VEGF通过调节内皮细胞活化反应的能力是同种氏菌排斥反应中的促炎细胞因子。我们的初步研究表明，VEGF仅增加内皮细胞趋化因子的产生，并与促炎性细胞因子结合使用。特别是，我们发现VEGF与IFN-gamma结合使用协同诱导T细胞趋化剂趋化因子IP-10的表达，已知在排斥反应中具有功能显着性。我们还在初步研究中发现，VEGF对于将同种反应性T细胞募集到同种异体移植物中是有效的。在这项研究建议中，我们将首次在同种免疫中确立VEGF的作用。我们建议将机械研究重点放在介导趋化因子产生的VEGF受体信号上，以及VEGF对NF-KB和STAT转录因子的影响相关的转录系列，以激活有效的T细胞趋化性IP-10。其次，我们计划研究VEGF在体外募集同种反应性T细胞方面的功能机理，第三我们将确定这些机制在体内同种异体移植排斥中是否重要。这些研究的结果应为新的治疗策略的未来发展提供有用的信息，并且还应为将VEGF识别为同种异体移植排斥的新目标奠定基础。

项目成果

Chemokine receptor trio: CXCR3, CXCR4 and CXCR7 crosstalk via CXCL11 and CXCL12.

• DOI: 10.1016/j.cytogfr.2012.08.007
• 发表时间: 2013-02
• 期刊: CYTOKINE & GROWTH FACTOR REVIEWS
• 影响因子: 13
• 作者: Singh, Anup Kumar;Arya, Rakesh Kumar;Trivedi, Arun Kumar;Sanyal, Sabyasachi;Baral, Rathindranath;Dormond, Olivier;Briscoe, David M.;Datta, Dipak
• 通讯作者: Datta, Dipak