Veto-ing the Rejection of Allogeneic HSCs

否决同种异体造血干细胞的拒绝

• 批准号: 7480973
• 负责人: Uwe D. Staerz
• 金额: $ 30万
• 依托单位: ISOGENIS, INC.
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-15 至 2010-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7480973
• 关键词: Adenovirus Vector; Adverse effects; Allogenic; Apoptosis; Bone Marrow; Bone Marrow Transplantation; CD4 Positive T Lymphocytes; CD8B1 gene; Cells; Child; Chronic; Condition; Dendritic Cells; Development; Disease; Engineering; Engraftment; Excision; Goals; Graft Rejection; Hematopoietic Stem Cell Transplantation; Hematopoietic stem cells; Homologous Transplantation; Human; Immune; Immune response; Immune system; In Vitro; Infusion procedures; Islets of Langerhans; Learning; Malignant - descriptor; Metabolic Diseases; Mission; Mus; Non-Malignant; Organ; Organ Transplantation; Population; Protocols documentation; Rate; Scientist; Solid; Surface; T-Lymphocyte; Technology; Tissues; Transplantation; Transplanted tissue; Treatment Protocols; United States Food and Drug Administration; Urination; antibody engineering; base; cell preparation; conditioning; design; gene transfer vector; graft failure; graft vs host disease; improved; in vivo; innovation; macrophage; novel; prevent; response; vector

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.

描述（申请人提供）：异基因造血干细胞（HSC）移植已成为恶性疾病的重要治疗手段。异基因造血干细胞移植（HSCT）被用于治疗其他血液病和一些代谢性疾病。同种异体HSCT代表完全或部分组织不相容的HSC的输注，其被接受者的免疫系统排斥。尽管有许多并发症，但接受者的苛刻预处理方案用于克服移植物排斥反应。目前正在寻求毒性更小、最好是短期的新方案;但如果没有提高疗效，也可以防止排斥反应。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的技术基于自然否决免疫抑制现象。Isogenis的工程否决不是注入供体来源的CD 8 + T细胞来抑制同种异体免疫反应，而是使用CD 8 α链的转移来将特异性免疫抑制活性附着到组织上，目的是保护它们免受排斥反应。Isogenis的科学家们确定了这种否决方法的总体可行性。工程抗体和不同的基因转移载体，否决载体（VV），用于证明表面表达的CD 8 α-链抑制T淋巴细胞反应在体外和体内，并最终保护胰岛从排斥反应在完全同种异体受体小鼠。Isogenis建议检查骨髓（BM）来源的细胞是否可以在Isogenis的VV的帮助下被工程化为有效的否决细胞。将研究工程化否决细胞是否防止同种异体HSC的排斥。如果成功，这种策略将允许移植高度纯化的HSC制剂。供体来源的T细胞的去除将避免移植物抗宿主病（GVHD），该移植物抗宿主病（GVHD）仅在用于非恶性疾病的HSCT的情况下是有害的，但将不再导致增加的移植失败率。Isogenis还提议研究BM衍生的工程否决细胞是否可以用于保护供体匹配的实体器官免受排斥。如果成功的话，Isogenis将只需要处理单个细胞群作为受监管的产品，而不是每个相应的移植器官。无关供者骨髓移植已成为恶性疾病的重要治疗方法。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直接和慢性副作用，使得它们的使用对于儿童尤其成问题。Isogenis正在开发新的免疫抑制化合物，毒性较小，短期使用;但预防移植组织的排斥反应，即使没有改善疗效，也具有相似的效果。