Induction of immune tolerance to FasL-expressing ES cell

诱导表达 FasL 的 ES 细胞的免疫耐受

• 批准号: 6879690
• 负责人: KAI CHRISTIAN SONNTAG
• 金额: $ 14.89万
• 依托单位: MCLEAN HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-01 至 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6879690
• 关键词: CD95 molecule; apoptosis; artificial immunosuppression; biotechnology; cell differentiation; cell line; clone cells; cyclosporines; embryonic stem cell; immune response; immune tolerance /unresponsiveness; immunoregulation; laboratory rat; ligands; mixed tissue /cell culture; pluripotent stem cells; stem cell transplantation; transfection /expression vector; transplant rejection; xenotransplantation

DESCRIPTION (provided by applicant): The potential of pluripotent embryonic stem (ES) cells to develop into functional mature cells or tissue has high implication in finding new treatments for diseases including neurodegenerative disorders. This includes the potential use of ES cells as cell replacement therapy in neurological diseases, such as Parkinson's Disease (PD), Huntington's Disease (HD), Amyotrophic Lateral Sclerosis (ALS) and ischemia. However, survival of call grafts requires systemic immunosuppression, which severely compromises the entire host immune system leading to complications in clinical transplantation. An optimal therapy would be, therefore, the induction of specific tolerance to the donor cells by otherwise preserving functional immune responses. Fas ligand (FasL, CD178, or CD95L) is a type II membrane protein and is expressed in activated lymphocytes and cells in "immune-privileged" sites such as the testis, the eye, and the CNS. Its receptor Fas (CD95 or Apo-1), a type I membrane protein and a member of the TNF receptor family, is expressed on various immune-reactive hematopoietic cell types including activated NK and T calls, non-lymphoid calls such as immature myeloid cells, monocytes, and polymorphic mononucleocytes. Fas-expressing cells undergo apoptosis upon interaction with FasL, a process that is involved in regulating cellular immunity and it has been shown that FasL can be used as an immunomodulatory tool to protect allogeneic or xenogeneic cells against cellular immune responses. Here, I hypothesize that ES cell grafts in the brain, which express FasL, are protected against the host cellular immune response abolishing the need for systemic immunosuppressive drug treatment. For this, I will genetically engineer mouse ES cells to express FasL and test their survival ability in the host brain of rats without further immunosuppression. Furthermore, I will analyze the effects of FasL expression on transplanted cells towards modulating the host immune response. Results from this work will have implications for immunomodulation of ES cell grafts in both allogeneic and xenogeneic transplantation settings.

描述（由申请人提供）：多能胚胎干（ES）细胞发育成功能性成熟细胞或组织的潜力对于寻找包括神经退行性疾病在内的疾病的新疗法具有重要意义。这包括ES细胞作为神经系统疾病的细胞替代疗法的潜在用途，例如帕金森病（PD）、亨廷顿病（HD）、肌萎缩侧索硬化症（ALS）和缺血。然而，移植物的存活需要全身免疫抑制，这严重损害了整个宿主免疫系统，导致临床移植并发症。因此，最佳疗法是通过保留功能性免疫反应来诱导对供体细胞的特异性耐受。 Fas 配体（FasL、CD178 或 CD95L）是一种 II 型膜蛋白，在活化的淋巴细胞和“免疫特权”部位（如睾丸、眼睛和中枢神经系统）的细胞中表达。其受体 Fas（CD95 或 Apo-1）是一种 I 型膜蛋白，也是 TNF 受体家族的成员，在各种免疫反应性造血细胞类型上表达，包括激活的 NK 和 T 细胞、非淋巴细胞细胞（例如未成熟骨髓细胞）细胞、单核细胞和多态性单核细胞。 Fas 表达细胞在与 FasL 相互作用后发生凋亡，这是一个参与调节细胞免疫的过程，并且已表明 FasL 可用作免疫调节工具来保护同种异体或异种细胞免受细胞免疫反应。在这里，我假设大脑中表达 FasL 的 ES 细胞移植物受到保护，免受宿主细胞免疫反应的影响，从而消除了全身免疫抑制药物治疗的需要。为此，我将对小鼠 ES 细胞进行基因改造，使其表达 FasL，并在不进一步免疫抑制的情况下测试其在大鼠宿主大脑中的生存能力。此外，我将分析 FasL 表达对移植细胞调节宿主免疫反应的影响。这项工作的结果将对同种异体和异种移植环境中 ES 细胞移植物的免疫调节产生影响。