Islet Transplantation - Protection by Immunobarriers

胰岛移植 - 免疫屏障的保护

• 批准号: 7039212
• 负责人: Gordon Campbell Weir
• 金额: $ 27.26万
• 依托单位: JOSLIN DIABETES CENTER
• 依托单位国家: 美国
• 财政年份: 1996
• 资助国家: 美国
• 起止时间: 1996-02-10 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7039212
• 关键词: NOD mouse; apoptosis; artificial membranes; autoimmunity; biomaterial development /preparation; cytoprotection; gene expression; genetically modified animals; homologous transplantation; immune tolerance /unresponsiveness; immunoregulation; laboratory mouse; laboratory rat; microcapsule; pancreatic islet function; pancreatic islet transplantation; polymerase chain reaction; technology /technique development; tissue /cell culture; transfection /expression vector; transforming growth factors; transplant rejection; transplantation immunology; xenotransplantation

DESCRIPTION (provided by applicant): Immunobarrier technology can protect transplanted islets from being destroyed by allorejection and autoimmunity. Considerable progress has been made in using simple alginate microcapsules. The goal of this proposal is to develop strategies to optimize transplantation outcomes with the expectation of encapsulating insulin-producing cells derived form precursor/stem cells. 1. Determine the factors that influence the survival of encapsulated islets. In spite of improved results with islet encapsulation remarkably little is known about the fate of encapsulated islets. We hypothesize that contributors to islet failure include trauma from islet isolation, central necrosis of large islets, and activation of a proinflammatory state that can activate the innate immune system and enhance the adaptive immune reaction. Learning more about these factors should lead to important new strategies to improve outcomes. 2. Use of a perfluorocarbon emulsion to improve oxygen delivery to transplanted encapsulated islets. Limited oxygen availability is a major problem for encapsulated islets, as this leads to a major loss of b-cells after transplantation. Large islets with diameters over 200 mu/m are especially vulnerable due to central hypoxia that leads to cell death. It is predicted that the use of a perfluorocarbon emulsion in capsules for improving oxygen delivery will prevent b-cell loss to hypoxia. 3. Develop methods to produce optimal sized islet cell aggregates that will preserve b-cell mass and limit the proinflammatory response. We predict it will be possible to determine the optimal diameter of islet cell aggregates that will prevent central hypoxia and improve packing density. Modeling should serve as a guide to optimal packing density for islet cell aggregates in capsules. In addition, it should be possible to create tissue culture conditions that will limit the proinflammatory state of aggregated cells. These predictions can be tested with dispersed rat islet cells that are aggregated in a controlled and defined manner. This work should serve as a guide for the encapsulation and transplantation of xenogeneic islets cells or insulin-producing cells that should eventually be produced from precursor/stem cells.

描述(由申请人提供)： 免疫屏障技术可以保护移植的胰岛免受同种排斥和自身免疫的破坏。在使用简单的海藻酸盐微胶囊方面已经取得了相当大的进展。这项提议的目标是开发优化移植结果的策略，期望封装来自前体细胞/干细胞的胰岛素产生细胞。 1.确定影响包膜胰岛存活的因素。尽管胰岛包裹的结果有了很大的改善，但人们对包裹的胰岛的命运知之甚少。我们推测导致胰岛衰竭的因素包括胰岛隔离造成的创伤、大胰岛的中央坏死，以及能够激活天然免疫系统和增强获得性免疫反应的促炎状态。更多地了解这些因素应该会导致制定重要的新战略，以改善结果。 2.使用全氟化碳乳剂改善移植包膜胰岛的氧气输送。对于包膜胰岛来说，有限的氧气供应是一个主要问题，因为这会导致移植后b细胞的主要损失。直径超过200亩/米的大胰岛特别容易受到中枢性缺氧导致细胞死亡的影响。据预测，在胶囊中使用全氟碳乳剂来改善氧气输送将防止b细胞因缺氧而丢失。 3.开发产生最佳大小的胰岛细胞聚集体的方法，以保存b细胞群并限制促炎反应。我们预测有可能确定胰岛细胞聚集体的最佳直径，以防止中心性缺氧和改善堆积密度。模型应作为胶囊中胰岛细胞聚集体的最佳堆积密度的指南。此外，应该有可能创造组织培养条件，限制聚集细胞的促炎状态。这些预测可以用以受控和定义的方式聚集的分散的大鼠胰岛细胞来检验。这项工作应该对最终应由前体/干细胞产生的异种胰岛细胞或产生胰岛素的细胞的封装和移植起到指导作用。