HUMAN ANTI PORCINE IMMUNE RESPONSES IN VIVO

人体内抗猪免疫反应

• 批准号: 6390899
• 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 2005-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6390899
• 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（根据调查员的摘要改编）：人类T的反应 对猪血管内皮的淋巴细胞将是决定的主要因素 临床组织或器官异种移植的结果。这种回应将会 可能由直接和间接认识的组合确定 在供体或受体MHC分子上表达的供体肽。研究的研究 体外反应表明异种人类抗孢子反应是 令人惊讶的是，比人类的同种响应强。相比之下，体内 实验模型表明，Xenoresponse明显弱于 同种答管。我们假设人内皮细胞上的某些蛋白质是 体内需要但不需要体外反应，该蛋白质（S） 由猪细胞表达较小程度或未被人t识别 细胞体内。研究人员已经发展了遗传的能力 具有高效率的病毒载体传递内皮细胞。这 以及合成胶原蛋白/纤连蛋白凝胶的发展 可以引入HUPBL/SCID米色鼠标模型的微血管系统 提供了一种在体内定义Xenorpognition属性的方法。具体 该提案的目的是：（1）牢固建立合成的微丝 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衍生的相互作用 体内的微量花序，（3）以遗传修改PAEC至过表达因子 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，（4） 利用信息来评估两个其他模型中的响应 在hupbl-scid中是小鼠：猪动脉移植和猪皮 接枝。这些实验将提供有关 T细胞在异种移植模型中的识别特性 异种移植。