PREVENTING ANTI-GAL PRODUCTION AGAINST XENOGRAFTS

防止异种移植物产生抗-Gal

• 批准号: 6287599
• 负责人: URI GALILI GALILI
• 金额: $ 25.17万
• 依托单位: RUSH UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-12-15 至 2003-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6287599
• 关键词: B cell receptor; B lymphocyte; alpha galactosidase; antigen antibody reaction; apoptosis; cell line; genetically modified animals; glycoproteins; immunoglobulin G; laboratory mouse; method development; ricin; transplant rejection; xenotransplantation

DESCRIPTION (verbatim from the applicant's abstract) The use of pig heart xenografts in humans may solve in the future the problem of paucity of heart allografts. Currently, binding of the human natural anti-Gal antibody to alpha-gal epitopes (Gal al-3Gal p14GlcNAc-R) on pig cells results in the immune rejection of xenografts. This obstacle can not be overcome by removal of anti-Gal by affinity columns, because this antibody returns to its normal level within few days. Furthermore, the xenograft recipient produces large amounts of high affinity anti-Gal IgG in response to alpha-gal epitopes on the xenograft. This elicited anti-Gal effectively mediates delayed and chronic rejection of xenografts. We propose to prevent anti-Gal production in xenograft recipients by specific elimination of B cells producing this antibody (designated anti-Gal B cells). This may be achieved by in vivo targeting of an alpha-gal coupled toxin, ricin A, (a-gal-ricin) to B cell receptors (BCR) on anti-Gal B cells, subsequent endocytosis of the toxin and death of these cells. Furthermore, the elimination of mature anti-Gal B cel}s may create a window of opportunity for long term prevention of maturation of these cells. Circulating glycoproteins expressing alpha-gal epitopes, continuously released from the xenograft, may bind to BCR on immature anti-Gal B cells and induce specific apoptosis of these B cells. We will test this hypothesis in alpha-l,3-galactosyltransferase knock-out (KO) mice . Our aims are 1) to define the optimal a-gal-ricin treatment protocol for elimination of mature anti-Gal B cells and plasma cells, 2) to determine whether infused alpha-gal glycoproteins, or such glycoproteins released from wild type mouse heart allografts, can induce long term elimination of immature anti-Gal B cells, and 3) to determine whether a-gal-ricin treatment can affect survival of pig single cell xenografts in KO mice. Success in these studies will help in planning effective treatments for preventing anti-Gal response in primate xenografts recipients. |

描述（来自申请人摘要的逐字记录）猪心的使用 人类异种移植可能在未来解决心脏缺乏的问题 同种异体移植目前，人天然抗Gal抗体与 猪细胞上的α-gal表位（Gal al-3Gal p14GlcNAc-R）导致免疫应答。 异种移植排斥反应。这一障碍不能通过消除 抗Gal亲和柱，因为该抗体恢复到其正常水平 在几天内。此外，异种移植物受体产生大量的 高亲和力抗-Gal IgG应答异种移植物上的α-gal表位。 这引起的抗Gal有效地介导了延迟和慢性排斥反应， 异种移植我们建议在异种移植受者中防止抗Gal产生 通过特异性消除产生这种抗体（称为抗Gal）的B细胞 B细胞）。这可以通过体内靶向α-gal偶联的 毒素蓖麻毒素A（α-半乳糖蓖麻毒素）对抗半乳糖B细胞上的B细胞受体（BCR）， 随后毒素的内吞作用和这些细胞的死亡。而且 成熟的抗Gal B细胞的消除可能会为 长期阻止这些细胞的成熟。循环糖蛋白 从异种移植物连续释放的表达α-gal表位的细胞可以 与未成熟抗Gal B细胞上的BCR结合并诱导这些细胞的特异性凋亡 B细胞。我们将在α-l，3-半乳糖基转移酶中检验这一假设 敲除（KO）小鼠。我们的目标是：1）确定最佳的α-半乳糖苷 用于消除成熟抗Gal B细胞和浆细胞的治疗方案， 2)为了确定是否输注的α-gal糖蛋白或这样的糖蛋白 从野生型小鼠心脏同种异体移植物中释放， 清除未成熟的抗Gal B细胞，和3）确定是否 α-半乳糖蓖麻毒素治疗可影响KO中猪单细胞异种移植物的存活 小鼠这些研究的成功将有助于制定有效的治疗方案， 预防灵长类异种移植物接受者中的抗Gal应答。 |