HUMAN ANTI PORCINE IMMUNE RESPONSES IN VIVO

人体内抗猪免疫反应

• 批准号: 6194807
• 负责人: ALFRED LM BOTHWELL
• 金额: $ 40.43万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-07-01 至 2001-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6194807
• 关键词: BCL2 gene /protein; Retroviridae; SCID mouse; T lymphocyte; blood vessel transplantation; capillary; cell cell interaction; collagen; fibronectins; gel; human tissue; selectins; skin transplantation; swine; transfection /expression vector; transplant rejection; vascular endothelium; xenotransplantation

DESCRIPTION (Adapted from Investigator's Abstract): The response of human T lymphocytes to porcine vascular endothelium will be a major factor determining the outcome of clinical tissue or organ xenotransplantation. This response will likely be determined by a combination of direct and indirect recognition of donor peptides expressed on donor or recipient MHC molecules. Studies of in vitro responses indicate the xenogenic human anti-porcine response is surprisingly stronger than the human alloresponse. By contrast, in vivo experimental models show that the xenoresponse is significantly weaker than the alloresponse. We hypothesize that some protein on human endothelial cells is required for in vivo but not in vitro responses and that this protein(s) expressed by porcine cells to a lesser degree or not recognized by human T cells in vivo. The investigators have developed the capacity to genetically transduce endothelial cells with viral vectors with high efficiency. This together with the development of a synthetic collagen/fibronectin gel microvessel system that can be introduced into huPBL/SCID beige mouse models offers a means to define properties of xenorecognition in vivo. The specific aims of this proposal are: (1) to firmly establish the synthetic microvessel using normal porcine aortic endothelial cells (PAEC) and Bcl-2 transduced Paec, (2) to characterize the interaction of human PBMC with porcine PAEC-derived microvessels in vivo, (3) to genetically modify PAEC to overexpress factors that affect T cell endothelial cell interactions and characterize the consequences in vivo and in the synthetic microvessel system in vivo, and (4) to utilize the information to evaluate the responses in two additional models in the huPBL-SCID being mouse: the porcine arterial graft and the porcine skin graft. These experiments will provide critical information regarding the recognition properties of T cells in a xenograft model that is essential for xenotransplantation.

描述（改编自研究者摘要）：人类 T 的反应 淋巴细胞对猪血管内皮的影响将是决定因素 临床组织或器官异种移植的结果。此回应将 可能是通过直接和间接认识的结合来确定的 供体肽在供体或受体 MHC 分子上表达。研究在 体外反应表明异种人抗猪反应是 令人惊讶的是，它比人类的同种异体反应更强。相比之下，体内 实验模型表明异种反应明显弱于 异体反应。我们假设人类内皮细胞上的某些蛋白质是 体内反应所需，但体外反应不需要，并且该蛋白质 猪细胞表达程度较低或不被人类 T 细胞识别 体内的细胞。研究人员已经开发出通过基因技术进行研究的能力 用病毒载体高效转导内皮细胞。这 以及合成胶原蛋白/纤连蛋白凝胶的开发 可引入 huPBL/SCID 米色小鼠模型的微血管系统 提供了一种定义体内异种识别特性的方法。具体的 该提案的目的是：（1）牢固地建立合成微血管 使用正常猪主动脉内皮细胞 (PAEC) 和 Bcl-2 转导的 Paec， (2) 表征人 PBMC 与猪 PAEC 来源的相互作用 体内微血管，(3) 对 PAEC 进行基因修饰以过度表达因子 影响 T 细胞内皮细胞相互作用并表征 体内和体内合成微血管系统的后果，以及（4） 利用这些信息来评估另外两个模型中的响应 huPBL-SCID 小鼠：猪动脉移植物和猪皮肤 接枝。这些实验将提供有关 异种移植模型中 T 细胞的识别特性对于 异种移植。