OPTIMIZATION OF HUMAN FETAL PANCREAS FOR TRANSPLANTATION

人类胎儿胰腺的移植优化

• 批准号: 6177141
• 负责人: HANS W SOLLINGER
• 金额: $ 24.78万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-09-01 至 2002-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6177141
• 关键词: antigen presentation; athymic mouse; autoimmunity; cell differentiation; cryopreservation; cytokine; diabetes mellitus therapy; embryo /fetus preservation; glucose; histogenesis; homologous transplantation; human fetus tissue; immunocytochemistry; insulin dependent diabetes mellitus; insulinlike growth factor; mixed tissue /cell culture; pancreas transplantation; pancreatic islet function; polymerase chain reaction; transcription factor; transplantation immunology

Human fetal pancreas (HFP) has the unique capacity for further growth and differentiation following transplantation to a diabetic recipient. The objective of our funded application was to determine the parameters required for the procurement, processing, storage, HLA typing, and testing for bacterial and viral contamination of HFP. We have achieved these goals and have established protocols for obtaining high quality tissue with good function. Our studies have advanced the field of HFP transplantation to the point where clinical trials can be, initiated. Three problems remain which limit the potential of HFP for successful clinical transplantation: 1) HFP requires up to three months following transplantation before acquisition of glucose responsiveness during which time it is not possible to monitor graft rejection, 2) HFP has a small mass of tissue and may require 20 or more pancreata for successful transplantation, and 3) HFP transplantation is subject to both allograft and autoimmune responses. Our long-term goal is to achieve successful HFP transplantation. Thus the objectives of this application are to: 1) Characterize both the allograft and autoimmune response to HFP and cellular subsets of HFP tissue. We will use mixed lymphocyte islet cell culture and specific lymphoid depletion to determine 1) the contribution of cellular and cytokine responses and 2) the role of direct and indirect antigen presentation to HFP graft loss. We will use this knowledge to design clinically relevant strategies for immunosuppressive therapy, 2) Accelerate the differentiation of HFP glucose responsiveness. We will use short-term culture and adenoviral-mediated gene transfer of specific growth and transcription factors to accelerate HFP differentiation and maturation, and 3) Demonstrate the potential to increase HFP beta cell mass in vitro with transient transformation of HFP with SV40-T antigen while maintaining beta cell function. We will use beta cell enriched HFP subpopulations infected with replication- defective adenovirus expressing SV40-T antigen to demonstrate the potential to increase beta cell mass without loss of HFP function. The results of these studies will provide a sufficient source of HFP tissue for clinical transplantation which responds to glucose challenge and requires minimal immunosuppressive therapy.

人胎儿胰腺（HFP）具有独特的进一步生长的能力 以及移植到糖尿病受体后的分化。 我们资助申请的目的是确定参数 采购、加工、储存、HLA分型所需的， 检测HFP的细菌和病毒污染。 我们已经取得 这些目标，并已建立协议，以获得高质量的 功能良好的组织。 我们的研究推动了HFP领域的发展 移植到可以开始临床试验的程度。 仍然存在三个问题，限制了HFP成功的潜力。 临床移植：1）HFP需要长达三个月的时间， 在获得葡萄糖反应性之前进行移植 此时不可能监测移植物排斥，2）HFP具有 小的组织块，可能需要20个或更多的胰腺才能成功 3）HFP移植受同种异体移植物 和自身免疫反应。 我们的长期目标是取得成功 HFP移植。 因此，本申请的目的是： 1)表征对HFP的同种异体移植和自身免疫反应， HFP组织的细胞亚群。我们将使用混合淋巴细胞胰岛细胞 培养和特异性淋巴细胞耗竭，以确定1） 细胞和细胞因子的反应和2）的作用，直接和 间接抗原呈递导致HFP移植物丢失。 我们将使用这个 设计临床相关免疫抑制策略的知识 2）促进HFP葡萄糖的分化 响应能力。 我们将使用短期培养和腺病毒介导的 特定生长和转录因子的基因转移，以加速 HFP分化和成熟，以及3）证明 瞬时转化提高体外HFP β细胞质量 与SV 40-T抗原的HFP，同时维持β细胞功能。 我们将 使用β细胞富集的HFP亚群感染复制- 表达SV 40-T抗原的缺陷型腺病毒，以证明 增加β细胞质量而不丧失HFP功能的潜力。 的 这些研究的结果将提供足够的HFP组织来源 用于响应葡萄糖挑战的临床移植， 需要最低限度的免疫抑制治疗。