Veto-ing the Rejection of Allogeneic HSCs

描述(申请人提供)：异基因造血干细胞(HSC)移植已成为治疗恶性疾病的重要手段。异基因造血干细胞移植(HSCT)正被用于治疗其他血液病和一些代谢性疾病。异基因造血干细胞移植代表输注完全或部分组织不相容的造血干细胞，这些干细胞被受者的免疫系统排斥。尽管有许多并发症，但受体的严苛调节方案被用来克服移植物排斥反应。人们正在寻求毒性较小、充其量是短期的新方案，但即使不是提高了疗效，也同样可以防止排斥反应。Isgenis的使命一直是开发创新的免疫抑制剂，采用高度特异但有效的免疫抑制方法。Isgenis的技术基于自然的否决权免疫抑制现象。Isgenis的转基因否决权不是注入供者来源的CD8+T细胞来抑制同种异体免疫反应，而是使用CD8 a链的转移来将特定的免疫抑制活性附加到组织上，目的是保护它们免受排斥。伊索吉尼斯的科学家确定了这种否决方法的总体可行性。利用基因工程抗体和不同的基因转移载体，否决权载体(VV)，证明CD8α链的表面表达在体内外抑制T淋巴细胞反应，最终保护完全同种异体受体小鼠的胰岛免受排斥反应。Isgenis建议研究是否可以在Isgenis的VVS的帮助下将骨髓(BM)来源的细胞工程化为有效的否决权细胞。将研究工程否决细胞是否能阻止异基因造血干细胞的排斥反应。如果成功，这一策略将允许移植高纯度的HSC制剂。去除供者来源的T细胞将避免移植物抗宿主病(GVHD)，而移植物抗宿主病只对非恶性疾病的HSCT有害，但不会再导致移植物失败率增加。Isgenis还建议研究骨髓来源的工程否决细胞是否可以用来保护与捐赠者匹配的实体器官免受排斥。如果成功，Isgenis将只需将单个细胞群体作为受监管产品处理，而不是处理每个单独的移植器官。非血缘关系供者的骨髓移植已成为治疗恶性疾病的重要手段。它还被用来治疗其他血液病和一些代谢性疾病。然而，目前用于器官移植的免疫抑制方案充满了显著的即时和慢性副作用，这使得它们的使用对儿童来说尤其成问题。Isgenis正在开发毒性较低、短期使用的新型免疫抑制化合物，但仍可防止移植组织的排斥反应，具有类似的效果(如果不是提高的话)。

DESCRIPTION (provided by applicant): The transplantation of allogeneic hematopoietic stem cells (HSC) has become an important treatment for malignant diseases. Allogeneic HSC transplantation (HSCT) is being used to provide cures for other hematological and also some metabolic diseases. Allogeneic HSCT represents the infusion of fully or partially histo-incompatible HSCs, which are rejected by the recipient's immune system. Harsh conditioning regimens of the recipient are used to overcome graft rejection in spite of numerous complications. New protocols are being sought that are less toxic and at best short-term; yet prevent rejection with similar if not improved efficacy. Isogenis' mission has been the development of innovative immune inhibitory agents that employ highly specific, yet effective immune suppression approaches. Isogenis based its technology on the natural veto immune inhibitory phenomenon. Rather than infusing donor-derived CD8+ T cells to suppress allogeneic immune responses, Isogenis' engineered veto uses the transfer of the CD8 a-chain to attach specific immune suppression activities to tissues with the goal to protect them from rejection. Isogenis' scientists established the overall feasibility of this veto approach. Engineered antibodies and different gene transfer vectors, veto vectors (VV), were used to demonstrate that surface expression of the CD8 a-chain inhibited T lymphocyte responses in vitro and in vivo and ultimately protected pancreatic islets from rejection in fully allogeneic recipient mice. Isogenis proposes to examine whether bone marrow (BM)-derived cells can be engineered into effective veto cells with the help of Isogenis' VVs. It will be investigated whether engineered veto cells prevent the rejection of allogeneic HSCs. If successful, this strategy will allow the transplantation of highly purified HSC preparations. The removal of donor-derived T cells will avoid graft-versus-host disease (GVHD) that are only detrimental in the case of HSCTs for non-malignant diseases, but will no longer result in increased graft failure rates. Isogenis also proposed to study whether BM-derived engineered veto cells can be used to protect donor-matched solid organs from rejection. If successful, Isogenis will only have to deal with a single cell population as regulated product rather than with each respective transplant organ. The transplantation of bone marrow from unrelated donors has become an important treatment for malignant diseases. Its also is being used to provide cures for other hematological and also some metabolic diseases. However, present immune suppression regimens used for organ transplantation are fraught with significant immediate and chronic side effects that make their use especially problematic for children. Isogenis is developing novel immune suppressive compounds that are less toxic, and are used short-term; yet prevent the rejection of transplanted tissue with similar if not improved efficacy.