Heart Xenotransplantation with Chimeric Donor Pigs

嵌合供体猪心脏异种移植

• 批准号: 6880332
• 负责人: WILLIAM Edward BESCHORNER
• 金额: $ 56.03万
• 依托单位: XIMEREX, INC.
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-01-01 至 2006-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6880332
• 关键词: artificial immunosuppression; baboons; bone marrow transplantation; electrocardiography; flow cytometry; heart transplantation; lymphocyte; polymerase chain reaction; splenectomy; swine; technology /technique development; tissue mosaicism; transplant rejection; xenotransplantation

DESCRIPTION (provided by applicant): The transplantation of heart grafts can dramatically provide a long and productive life to recipients with heart failure. Typical transplant survivals are more than 10 years. Because of an acute shortage of human donors, however, most do not receive their needed heart graft. Whereas approximately 2300 transplants are performed annually in the United States, it has been estimated that 50,000 could benefit, if a donor were available. In the developed world, the unmet need is estimated at 135,000 transplants per year. The use of donor pigs could readily resolve this severe shortage of organ donors. Pigs can be raised under very clean conditions and would eliminate the risk of spreading human infections and tumors. The physiology of the pig heart is also very similar to human hearts. However, pig heart xenografts are vigorously rejected. With conventional and transgenic donor pigs, increased immune suppression is required to prolong graft survival. This has raised concern about transmission of zoonotic infections to the recipient. The problem is that multiple immune reactions by the host against multiple xenoantigens destroy the graft. Ximerex, Inc. has developed proprietary technology that prevents acute xenograft rejection, including acute vascular rejection, without the need for severe immune suppression. By growing the recipient lymphocytes within donor fetal pigs, the goals of transplantation, specific immune tolerance to the pig and accommodation of the pig tissues, are achieved within the donor animal, before transplantation. Ximerex would process and grow the patient's marrow cells in the donor pig and provide chimeric spleen lymphocytes and an accommodated donor heart to the transplant center. The value of chimeric donor pigs has been demonstrated with pig to sheep heart transplants, including transplants into sensitized sheep with preformed anti-pig antibodies. With modest immune suppression, prolonged graft survival was observed. Furthermore, prolonged survival of pig islets (>150 days) in rhesus macaques was achieved without any post-transplant immune suppression. Heart explants from chimeric pigs demonstrate accommodation with protection against antibodies and complement, including fresh human blood. RNA for proteins associated with accommodation is upregulated in the heart tissue. The proposed SBIR project would complete the preclinical studies required for FDA allowance of phase I/II clinical trials. The Phase I SBIR proposal would establish in pilot studies the efficacy of transplanting chimeric donor pig hearts into non-human primates with hide or no immune suppression. Follow up studies would establish the relative contribution of tissue accommodation and specific immune tolerance to the prolongation of heart xenograft survival.

描述（由申请人提供）：心脏移植物的移植可以显著地为患有心力衰竭的受者提供长期和富有成效的生活。典型的移植存活期超过10年。然而，由于人类捐赠者的严重短缺，大多数人都没有得到他们所需要的心脏移植。在美国，每年大约进行2300例移植手术，如果有捐赠者，估计有50，000例可以受益。在发达国家，未满足的需求估计为每年135 000例移植。使用供体猪可以很容易地解决器官供体严重短缺的问题。猪可以在非常干净的条件下饲养，并消除传播人类感染和肿瘤的风险。猪心脏的生理学也与人类心脏非常相似。然而，猪心异种移植物被强烈排斥。对于常规和转基因供体猪，需要增加免疫抑制以延长移植物存活。这引起了人们对人畜共患病传染给接受者的关注。问题是宿主对多种异种抗原的多重免疫反应会破坏移植物。 Ximerex，Inc.该公司开发了专有技术，可以防止急性异种移植排斥反应，包括急性血管排斥反应，而不需要严重的免疫抑制。通过在供体胎猪内培养受体淋巴细胞，在移植之前，在供体动物内实现移植的目标、对猪的特异性免疫耐受和猪组织的适应。Ximerex将在供体猪中处理和培养患者的骨髓细胞，并向移植中心提供嵌合脾淋巴细胞和适应的供体心脏。嵌合供体猪的价值已经通过猪到羊的心脏移植得到了证明，包括移植到预先形成抗猪抗体的致敏羊中。在适度的免疫抑制下，观察到移植物存活延长。此外，猪胰岛在恒河猴中的存活期延长（>150天），而没有任何移植后免疫抑制。来自嵌合体猪的心脏外植体表现出对抗体和补体的保护的适应性，包括新鲜的人血。与调节相关的蛋白质的RNA在心脏组织中上调。 拟议的SBIR项目将完成FDA批准I/II期临床试验所需的临床前研究。第一阶段SBIR提案将在试点研究中确定将嵌合供体猪心脏移植到具有隐藏或没有免疫抑制的非人灵长类动物中的功效。后续研究将确定组织适应性和特异性免疫耐受对延长异种心脏移植物存活的相对贡献。