HUMAN ANTI PORCINE IMMUNE RESPONSES IN VIVO

人体内抗猪免疫反应

• 批准号: 6755172
• 负责人: ALFRED LM BOTHWELL
• 金额: $ 40.88万
• 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 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6755172
• 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《调查者摘要》)：人类T的反应 淋巴细胞对猪血管内皮细胞的作用将是一个主要的决定因素 临床异种组织或器官移植的结果。此响应将 可能由直接和间接识别的组合来确定 在供体或受体MHC分子上表达的供体多肽。In的研究 体外反应表明异种人抗猪反应是 比人类的同种异体反应强得多。相比之下，在活体内 实验模型表明，异种反应明显弱于 异种反应。我们假设人内皮细胞上的某些蛋白质是 这是体内反应所必需的，但不是体外反应所需的，而且这种蛋白(S) 猪细胞表达程度较低或不被人T细胞识别 体内的细胞。研究人员已经开发出了从基因上 用病毒载体高效转导内皮细胞。这 以及合成胶原/纤维连接蛋白凝胶的开发 可导入HuPBL/SCID褐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 这项建议的目的是：(1)牢固地建立合成微血管 用正常猪主动脉内皮细胞(PAEC)和Bcl2转导的PAEC， (2)人PBMC与猪PAEC来源的相互作用的研究 体内微血管，(3)基因修饰血管内皮细胞过表达因子 影响T细胞与内皮细胞的相互作用，并表征 在体内和体内合成微血管系统中的后果，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 嫁接。这些实验将提供关于 T细胞在异种移植模型中的识别特性 异种移植。