SURROGATE TOLEROGENESIS IN XENOTRANSPLANTATION

目前，可用的人体器官严重短缺，而且日益严重。 捐助者。最近，相当大的兴趣集中在使用猪作为 一个潜在的移植器官来源一旦超急性排斥反应， 很明显，暴发性急性排斥反应是主要的 阻碍猪器官异种移植广泛应用的障碍。严重 防止这种排斥反应所需的免疫抑制将导致 高得令人无法接受的死亡率。 我们提出了一种新的异种移植方法，称为“替代 “耐受发生”是指在器官受体外诱导耐受， 在动物器官捐献者体内。这将大大减少对 免疫抑制使用绵羊作为器官的初始I期结果 事实上，接受者支持这一主张， 仅以最小抑制实现存活。使用大型动物 异种移植模型，拟议的研究将进一步发展， 评价替代耐受性，为初始临床试验做准备 肾脏移植的研究。 具体目标是： 1.评价替代耐受发生的潜在改善。 2.评估代孕的长期潜力和并发症 耐受发生 3.确定在不一致异种移植模型中的有效性。 4.确定耐受性转移所必需的细胞群 回到接受者。 拟定商业应用： 由于人体器官捐献者的严重短缺， 猪异种移植物的效果很好。肾移植是成本效益 与血液透析相比， 人的肾脏这项技术可以节省大量资金， 移植到那些没有供体的人身上，并通过最大限度地减少免疫并发症， 镇压该技术也适用于其他器官移植，如 如心脏、肝脏等。

There is presently a severe and growing shortage of available human organ donors. Considerable interest has focused recently on the use of pigs as a potential source of transplant organs. Once hyperacute rejection was prevented, it became apparent that fulminant acute rejection is the major obstacle blocking the widespread use of pig organ xenografts. The severe immune suppression required to prevent this rejection would lead to an unacceptably high mortality rate. We have proposed a new approach to xenotransplantation, called "surrogate tolerogenesis" where tolerance is induced outside of the organ recipient, within the animal organ donor. This should greatly decrease the need for immune suppression. Initial phase I results using sheep as organ recipients, in fact, supported this proposition, where prolonged graft survival was achieved with only minimal suppression. Using large animal xenotransplant models, the proposed studies will further develop and evaluate surrogate tolerogenesis, in preparation for initial clinical studies of kidney transplants. The specific aims are to: 1. Evaluate potential improvements of surrogate tolerogenesis. 2. Assess the long term potential and complications of surrogate tolerogenesis. 3. Determine effectiveness in a discordant xenotransplant model. 4. Determine the cell populations essential for the transfer of tolerance back to the recipient. PROPOSED COMMERCIAL APPLICATION: As defined by the severe shortage of human organ donors, the demand for pig xenografts is expected to be great. Kidney grafts are cost effective compared with hemodialysis, but the savings is limited by the shortage of human kidneys. This technology could save considerable funds by providing grafts to those without donors and by minimizing complications from immune suppression. The technology would also apply to other organ grafts, such as heart, liver, etc.