Islet Transplantation - Protection by Immunobarriers

描述（由申请人提供）： 免疫屏障技术可以保护移植胰岛免受同种异体排斥反应和自身免疫的破坏。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。该提案的目标是制定策略，以优化移植结果，并期望封装来自前体/干细胞的胰岛素产生细胞。 1.确定影响包囊胰岛存活的因素。尽管胰岛包裹的结果得到了改善，但对包裹的胰岛的命运知之甚少。我们假设胰岛衰竭的原因包括胰岛分离的创伤、大胰岛的中央坏死以及可以激活先天免疫系统并增强适应性免疫反应的促炎状态的激活。更多地了解这些因素应该会导致重要的新战略，以改善结果。 2.使用全氟化碳乳剂改善向移植的包封胰岛的氧输送。有限的氧气可用性是囊化胰岛的主要问题，因为这导致移植后b细胞的大量损失。直径超过200 mu/m的大胰岛由于导致细胞死亡的中心缺氧而特别脆弱。据预测，在胶囊中使用全氟化碳乳剂以改善氧气输送将防止b细胞因缺氧而丧失。 3.开发生产最佳大小的胰岛细胞聚集体的方法，以保留b细胞群并限制促炎反应。我们预测将有可能确定胰岛细胞聚集体的最佳直径，这将防止中心缺氧并提高堆积密度。模型应作为指导胰岛细胞聚集体在胶囊中的最佳包装密度。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。这些预测可以用分散的大鼠胰岛细胞进行测试，这些细胞以受控和限定的方式聚集。这项工作应作为指导封装和移植异种胰岛细胞或胰岛素产生细胞，最终应产生的前体/干细胞。

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.