Heart Xenotransplantation with Chimeric Donor Pigs

描述（由申请人提供）：心脏移植可以显著延长心力衰竭患者的生命。典型的移植存活时间超过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的心脏移植。在美国，每年大约有2300例移植手术，据估计，如果能找到捐赠者，将有5万例移植手术受益。在发达国家，未满足的移植需求估计为每年13.5万例。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，这将消除人类感染和肿瘤传播的风险。猪心脏的生理机能也与人类的心脏非常相似。然而，猪心脏异种移植被强烈排斥。对于传统和转基因供体猪，需要增加免疫抑制来延长移植物存活。这引起了人们对人畜共患病传染给接受者的担忧。问题是宿主针对多种异种抗原的多重免疫反应会破坏移植物。

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.