PANCREATIC ISLET XENOGRAFT TRANSPLANTATION

这一建议主要涉及使用 分离的胰岛或粗制胰腺的一致异种移植物 在自发性糖尿病和 链脲佐菌素诱导的糖尿病动物模型。 以下方法将 用于诱导糖尿病宿主接受胰岛异种移植物：1） 直接UV照射分离的胰岛和粗制的胰腺细胞; 2)移植前和移植后用紫外线处理宿主的效果 照射的供体特异性血液成分; 3）（1）和 (2)和4）附加的移植物周围处理宿主， 免疫抑制过程，特别是环孢菌素。 第二部分 该提案的主要问题是使用 同种移植物、同种异体移植物和异种移植物中的胰岛粗制品， 而不是孤立的胰岛，以避免低产量和 胰岛分离不充分，使得胰腺的临床有用性 胰岛移植仍然相对不切实际。 的体外研究 从移植物中消耗“刺激细胞”以及这种细胞的作用， 异种移植模型中的细胞将与 以上研究。 该提案的目标是开发一种方法， 供体胰岛细胞和糖尿病宿主的移植前治疗， 这将导致1）供体特异性延长的异种移植物存活; 2） 避免移植后的标准免疫抑制; 3）保留宿主 对其他抗原的免疫活性;和4）阐明机制 参与了紫外线照射对胰岛异种移植物接受的影响。 拟议的研究预计将证明紫外线照射将 有效改变胰岛或粗品的免疫原性， 异种移植模型中的胰岛制备物。 中概述的方法的使用 这一建议可能对胰岛具有主要的临床应用性 因为1）它们涉及使用异种胰岛 组织，可以解决供体胰岛的供应问题， 临床移植; 2）它们涉及直接治疗 移植物或供体型血液成分，两者均无任何毒性 对糖尿病宿主; 3）它们可能直接导致 胰岛同种异体移植物和特别是人类的一致异种移植物，其中 本提案中概述的方法将易于适用且安全， 已经成功地诱导和维持了胰岛 在啮齿类动物的糖尿病模型中进行同种异体移植。

This proposal concerns itself primarily with the possibility of using concordant xenografts of isolated pancreatic islets or crude pancreatic digests in reversing diabetes mellitus in spontaneously diabetic and streptozotocin-induced diabetic animal models. The following methods will be used to induce islet xenograft acceptance by the diabetic host: 1) direct UV irradiation of isolated islets and of crude pancreatic digests; 2) the effect of pre- and post-transplant treatment of the host with UV irradiated donor-specific blood components; 3) a combination of (1) and (2); and 4) additional peritransplant treatment of the host with a brief course of immunosuppression, particularly Cyclosporin. In the second part of this proposal the primary issue addressed is the possibility of using crude islet preparations in isografts, allografts and xenografts, rather than isolated islets, in order to avoid the problems of low yield and insufficient islet isolation that makes clinical usefulness of pancreatic islet transplantation still relatively impractical. In vitro studies of the depletion of 'stimulating cells' from the graft and the role of such cells in the xenograft model will be investigated in parallel with the above studies. The goal of this proposal is to develop a method of pretransplant treatment of the donor islet cells and of the diabetic host, which will result in 1) donor-specific prolonged xenograft survival; 2) avoidance of standard immunosuppression post-grafting; 3) retention of host immunocompetence to other antigens; and 4) clarification of mechanisms involved in the effect of UV irradiation on islet xenografts acceptance. The proposed studies are expected to demonstrate that UV irradiation will be effective in altering the immunogenicity of pancreatic islets or crude islet preparations in xenograft models. The use of the methods outlined in this proposal may have major clinical applicability to pancreatic islet transplantation in man since 1) they involve the use of xenogeneic islet tissue which could obviate the problem of supply of donor islets in clinical transplantation; 2) they involve either direct treatment of the graft or of donor type blood components, neither of which has any toxicity to the diabetic host; and 3) they may lead directly to initial trials of islet allografts and particularly concordant xenografts in man, where the methods outlined in this proposal would be readily applicable and safe, and have already been successful in induction and maintenance of islet allografts in some models of diabetes in rodents.