Protection of Hepaticyte Transplants by Engineered Veto

描述（由申请人提供）：自从引入肝移植以来，患者和移植物结局逐渐改善。全肝或节段性肝移植已经在患有不同的获得性和遗传性肝病的患者中进行。已经研究了分离肝细胞的输注作为实体器官移植的替代方法。同种异体肝细胞的移植已经成功地进行，以减轻遗传缺陷和肝功能衰竭的症状。在某些情况下，这些治疗是治愈性的，而在另一些情况下，这些治疗提供了缓刑，直到有实体器官可用。一般免疫抑制方案已被用于保护同种异体肝组织免受排斥。虽然成功，但它们充满了许多严重的副作用。最突出的是，它们损害免疫系统的保护功能。因此，正在做出重大努力来引入新的治疗剂，其以类似的（如果不是改善的）功效保护同种异体移植物，但毒性较小，高度特异性，不抑制保护性免疫应答，并且最多必须瞬时提供。Isogenis的技术基于自然否决免疫抑制现象。Isogenis的工程否决使用CD8？链将细胞和细胞转化为特异性免疫抑制实体。Isogenis认为，其否决技术将改变免疫抑制的模式，从系统性（一般）到组织特异性（组织中心）。Isogenis的科学家们用工程抗体和不同的否决载体（VV）建立了否决方法的整体可行性。Isogenis现在建议检查肝细胞是否可以用VV转导，并且可以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。肝细胞具有低免疫原性，它们可以相对容易地离体操作，并且在大多数情况下，它们的植入不会因潜在的自身免疫性疾病过程而复杂化。Isogenis将为未来的II期SBIR资助奠定基础，其中Isogenis将使用非人灵长类动物模型来测试临床VV的功能性，药理学和毒性，从而旨在完成肝细胞移植的临床前试验阶段。已开始与美国食品和药物管理局（FDA）讨论VV及其在移植中的使用。肝脏和肝细胞移植已成功地在患有不同的获得性和遗传性肝病的患者中进行。一般免疫抑制方案已被用于保护同种异体肝组织免受排斥。虽然成功，但它们充满了许多严重的副作用。最突出的是，它们损害免疫系统的保护功能。Isogenis一直在开发新的治疗方法，以类似的方式保护同种异体移植物，如果没有提高疗效，但毒性较小，高度特异性，不抑制保护性免疫反应，最好是暂时提供。

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.