Protection of Hepaticyte Transplants by Engineered Veto

描述(由申请人提供)：自从引入肝移植以来，患者和移植物的结果逐渐改善。对于患有不同获得性和遗传性肝病的患者，已经进行了全肝或节段性肝移植。输注分离的肝细胞作为实体器官移植的替代方法已被研究。同种异体肝细胞移植已经成功地用于缓解遗传缺陷和肝功能衰竭的症状。它们在某些情况下是治愈的，在其他情况下提供缓刑，直到固体器官可用。一般的免疫抑制方案已被用于保护同种异体肝组织免受排斥反应。尽管取得了成功，但它们也存在许多严重的副作用。最明显的是，它们损害了免疫系统的保护功能。因此，人们正在努力引入新的治疗方法，以保护同种异体移植物，即使不是提高了疗效，也是类似的，但毒性较低，特异性高，不会抑制保护性免疫反应，最多只能暂时提供。Isgenis的技术是基于自然的否决权免疫抑制现象。Isgenis的工程否决权使用CD8链的表面表达来将细胞和细胞转化为特定的免疫抑制实体。Isgenis认为，其否决技术将改变免疫抑制的范式，从全身性(一般)到组织特异性(组织中心)。Isgenis的科学家利用基因工程抗体和不同的否决权载体(VV)建立了否决权方法的总体可行性。Isgenis现在建议检查VVS是否可以转导肝细胞，并能够永久保护同种异体宿主免受排斥反应。肝细胞移植可能是理想的模型。肝细胞的免疫原性较低，可以相对容易地在体外进行操作，在大多数情况下，它们的植入不会因潜在的自身免疫性疾病过程而复杂化。Isgenis将为未来的第二阶段SBIR拨款奠定基础，在该阶段，Isgenis将使用非人类灵长类动物模型来测试临床VV的功能、药理和毒性，从而旨在完成肝细胞移植的临床前试验阶段。已经开始与食品和药物管理局(FDA)讨论VVS及其在移植中的使用。肝和肝细胞移植已经成功地用于患有不同获得性和遗传性肝病的患者。一般的免疫抑制方案已被用于保护同种异体肝组织免受排斥反应。尽管取得了成功，但它们也存在许多严重的副作用。最明显的是，它们损害了免疫系统的保护功能。Isgenis一直在开发保护同种异体移植物的新疗法，这些疗法即使没有提高疗效，也具有类似的疗效，但毒性更低，特异性更高，不会抑制保护性免疫反应，最多只能暂时提供。

DESCRIPTION (provided by applicant): Since the introduction of liver transplantation, patient and graft outcomes have incrementally improved. Whole liver or segmental liver transplantation have been performed in patients suffering from different acquired and genetic liver diseases. The infusion of isolated hepatocytes has been investigated as an alternative to solid organ grafting. Transplantations of allogeneic hepatocytes have been successfully performed to alleviate symptoms of genetic defects and liver failures. They were curative in some cases and provided reprieve in other cases until solid organs became available. General immune suppression regimens have been used to protect allogeneic liver tissues from rejection. Though successful, they are fraught by many grave side effects. Most prominently they impair the protective functions of the immune system. Therefore, major efforts are being made to introduce novel therapeutics that protect allogeneic grafts with similar, if not improved efficacy, yet that are less toxic, highly specific, do not suppress protective immune responses and at best have to be provided transiently. Isogenis bases its technology on the natural veto immune inhibitory phenomenon. Isogenis' engineered veto uses the surface expression of the CD8 ?- chain to transform cells and cells into specifically immune suppressive entities. Isogenis believes that its veto technology will change the paradigm of immune suppression from systemic (general) to tissue specific (tissue centered). Isogenis' scientists established the overall feasibility of the veto approach with engineered antibodies and different veto vectors (VV). Isogenis now proposes to examine whether hepatocytes can be transduced with VVs and can be permanently protected from rejection in allogeneic hosts. Hepatocyte transplantation may represent the ideal model. Hepatocytes are of low immunogenicity, they can be manipulated ex vivo with relative ease and in most cases their engraftment is not complicated by underlying autoimmune disease processes. Isogenis will lay the foundation for a future Phase II SBIR grant, in which Isogenis will use a nonhuman primate model to test the functionality, pharmacology and toxicity of a clinical VV and thus will aim to complete the pre-clinical trial stage of hepatocyte transplantation. Discussions with the Food and Drug Administration (FDA) about VVs and their use in transplantation have been initiated. Liver and hepatocyte transplantations have successfully been performed in patients suffering from different acquired and genetic liver diseases. General immune suppression regimens have been used to protect allogeneic liver tissues from rejection. Though successful, they are fraught by many grave side effects. Most prominently they impair the protective functions of the immune system. Isogenis has been developing novel therapeutics that protect allogeneic grafts with similar, if not improved efficacy, yet that are less toxic, highly specific, do not suppress protective immune responses and at best have to be provided transiently.