PANCREATIC ISLET XENOGRAFT TRANSPLANTATION

这项提议主要涉及到使用 游离胰岛或粗制胰腺的融合性异种移植 自发性糖尿病和自发性糖尿病患者的消化不良 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异种胰岛移植：1) 离体胰岛和粗制胰腺消化液的直接紫外线照射； 2)移植前后紫外线照射对宿主的影响 辐照的献血者特定血液成分；3)(1)和 (2)；和4)对宿主的附加移植围手术期处理 免疫抑制的疗程，特别是环孢素。第二部分 在这项提议中，解决的主要问题是使用 同种异体移植物、异体移植物和异种移植物中的粗制胰岛制剂 而不是孤立的小岛，以避免产量低和 胰岛分离不足，使胰腺在临床上有用 胰岛移植仍然相对不切实际。人血清白蛋白的体外研究 移植物中“刺激细胞”的耗尽及其作用 异种移植模型中的细胞将在研究的同时进行 以上研究。这项提议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)供者特异性延长异种移植物存活时间；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；以及4)机制的阐明 参与紫外线照射对异种胰岛移植物接受性的影响。 拟议中的研究预计将证明紫外线照射将 有效地改变胰岛或粗制胰岛的免疫原性 异种移植模型中的胰岛制备。中概述的方法的使用 这一建议可能对胰岛具有重要的临床适用性。 人的移植因为1)它们涉及异种胰岛的使用 可以避免供体胰岛供应问题的组织 临床移植；2)它们涉及要么直接治疗 移植物或供血型血液成分，两者均无任何毒性 对糖尿病宿主；以及3)它们可能直接导致对 人同种异体胰岛移植，尤其是协调性异种移植 本提案中概述的方法将很容易适用和安全，并且 已经成功地诱导和维持了胰岛 某些啮齿动物糖尿病模型中的同种异体移植。

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.