PREVENTION OF HYPERACUTE REJECTION IN AN EX-VIVO PIG TO HUMAN CARDIAC XENOGRAFT

预防离体猪对人心脏异种移植物的超急性排斥反应

• 批准号: 6114062
• 负责人: Jonathan P Fryer
• 金额: $ 2.05万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-12-01 至 1999-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6114062
• 关键词: binding proteins; cardiovascular transplantation; complement pathway; disease /disorder prevention /control; human tissue; perfusion; swine; synthetic peptide; transplant rejection; xenotransplantation

Because of the severe shortage of available human organs for donation, other species have been considered as potential donors for human transplantation. Of the options available, the pig appears to be the most suitable candidate. Hyperacute rejection has been a major barrier to pig-to-human transplantation, although several strategies have been successful in preventing this. Despite preventing hyperacute rejection, delayed xenografic rejection occurs which is characterized by endothelial cell activation and invasion of macrophages and natural killer cells. Although many of the successful strategies to avert hyperacute rejection have used approaches which prevent complete activation of the complement cascade, none have attempted to inhibit the complement cascade in its earliest phases. Deposition of the initial components of the complement cascade (C1, C4, C2) can lead to the accumulation of inflammatory cells and may contribute to endothelial cell activation thus creating a situation which is consistent with delayed xenograft rejection. Using novel synthetic peptides (complementary binding peptides) developed at Northwestern University, we will attempt to block the deposition of the early components of the complement cascade, thus preventing hyperacute rejection as well as the pro-inflammatory stimulus which is elicited from these early components. This will be tested in an ex vivo perfusion circuit where human blood is perfused through a pig heart with and without the complementary binding peptides.

由于可供捐赠的人体器官严重短缺，其他物种被认为是人类移植的潜在供体。 在现有的选择中，猪似乎是最合适的候选人。 超急性排斥反应一直是猪到人移植的主要障碍，尽管有几种策略已经成功地预防了这一点。 尽管预防了超急性排斥反应，但发生了延迟性异种移植排斥反应，其特征在于内皮细胞活化以及巨噬细胞和自然杀伤细胞的侵入。虽然许多成功的策略，以避免超急性排斥反应已使用的方法，防止补体级联反应的完全激活，没有试图抑制补体级联反应在其最早的阶段。 补体级联反应的初始组分（C1、C4、C2）的沉积可导致炎性细胞的积聚，并可能导致内皮细胞活化，从而产生与延迟性异种移植排斥一致的情况。 使用西北大学开发的新型合成肽（互补结合肽），我们将试图阻止补体级联反应早期组分的沉积，从而防止超急性排斥反应以及这些早期组分引起的促炎刺激。 这将在离体灌注回路中进行测试，其中人血通过猪心脏灌注，具有和不具有互补结合肽。