Veto-ing the Rejection of Allogeneic HSCs

描述（申请人提供）：同种异体造血干细胞（HSC）移植已成为恶性疾病的重要治疗手段。同种异体造血干细胞移植（HSCT）正被用于治疗其他血液学疾病和一些代谢疾病。同种异体造血干细胞移植是输注完全或部分组织不相容的造血干细胞，这些造血干细胞会被受体的免疫系统排斥。尽管有许多并发症，受体的严酷调理方案被用来克服移植排斥。目前正在寻求毒性更小、充其量是短期的新方案；然而，防止排斥的效果即使没有提高，也是相似的。Isogenis的使命是开发创新的免疫抑制剂，采用高度特异性，但有效的免疫抑制方法。Isogenis基于自然否决免疫抑制现象的技术。Isogenis的工程否决不是注入供体来源的CD8+ T细胞来抑制异体免疫反应，而是利用CD8 a链的转移将特定的免疫抑制活性附着在组织上，目的是保护它们免受排斥。Isogenis的科学家确定了这种否决方法的总体可行性。利用工程抗体和不同的基因转移载体否决载体（veto vector， VV）证明了CD8 a链的表面表达在体外和体内抑制T淋巴细胞反应，并最终保护完全异体受体小鼠的胰岛免受排斥反应。Isogenis提出在Isogenis的VVs的帮助下，研究骨髓（BM）来源的细胞是否可以被改造成有效的否决细胞。它将被研究是否工程否决细胞防止排斥异体造血干细胞。如果成功，这一策略将允许移植高度纯化的HSC制剂。移除供体来源的T细胞将避免移植物抗宿主病（GVHD），这种病仅在非恶性疾病的移植中有害，但不会再导致移植物失败率增加。Isogenis还建议研究脑基衍生的工程否决细胞是否可用于保护供体匹配的实体器官免受排斥。如果成功，Isogenis将只需要处理单个细胞群作为调节产物，而不是处理每个移植器官。非亲属骨髓移植已成为恶性疾病的重要治疗手段。它也被用于治疗其他血液病和一些代谢疾病。然而，目前用于器官移植的免疫抑制方案充满了显着的即时和慢性副作用，使其对儿童的使用尤其成问题。Isogenis正在开发毒性较小、短期使用的新型免疫抑制化合物；然而，防止排斥的移植组织与类似的，如果没有提高疗效。

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.