MARROW GRAFT REJECTION IN ALLOGENEIC BONE MARROW TRANSPLANTATION

同种异体骨髓移植中的骨髓移植排斥

• 批准号: 3774400
• 负责人: R E GRESS
• 金额: --
• 依托单位: DIVISION OF CANCER BIOLOGY AND DIAGNOSIS
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3774400
• 关键词: CD3 molecule; antireceptor antibody; biological response modifiers; bone marrow transplantation; clone cells; cytotoxic T lymphocyte; histocompatibility antigens; homologous transplantation; interleukin 2; laboratory mouse; leukocyte activation /transformation; major histocompatibility complex; monoclonal antibody; radiation immunosuppression; suppressor T lymphocyte; transplant rejection

A number of observations have suggested that host lymphocytes, specifically cytotoxic T cells (CTL) may play a significant role in mediating allogeneic marrow graft rejection. In a murine model system, CTL were cloned from the spleens of sublethally irradiated animals which had rejected MHC disparate marrow grafts. It was found that cloned CTL were sufficient to effect rejection of T cell depleted allogeneic marrow in lethally irradiated animals. The rejection of marrow grafts by CTL was specific for the MHC gene products expressed by the marrow cells and correlated with the cytotoxic specificity of the individual clones. Because host CTL in isolation could reject donor marrow grafts, effects on engraftment by (l) cell populations able to suppress host CTL responses, and (2) the administration of anti-CD3 monoclonal antibody in vivo, which by previous work had been shown to suppress CTL function, were studied. Cells with a specific type of suppressor activity, termed veto cells, which might suppress host rejection responses, have been reported to be present in marrow. The ability of lL-2 to enhance the activity of veto suppressor cell populations remaining in marrow after T cell depletion was investigated in vitro and in vivo. It was found that the incubation of T cell depleted marrow with IL-2 significantly increased veto activity as assessed by in vitro assays and also enhanced engraftment of MHC- mismatched, T cell depleted marrow in vivo, and that veto cells exerted their effect by clonal deletion of precursor CTL. Such clonal elimination involved participation by precursor CTL as well as veto cells. In further studies of engraftment of T cell depleted allogeneic marrow, host mice were treated with anti-CD3 monoclonal antibody. Marked enhancement of engraftment was observed; this effect on engraftment was enduring and due to suppression of host T cell function and to the release of multiple cytokines associated with in vivo activation of T cells by anti-CD3 antibody.

大量观察表明宿主淋巴细胞， 特别是细胞毒性 T 细胞 (CTL) 可能在 介导同种异体骨髓移植排斥反应。在小鼠模型系统中，CTL 是从受亚致死辐射的动物的脾脏中克隆出来的 拒绝 MHC 不同的骨髓移植物。结果发现，克隆的CTL 足以影响 T 细胞耗尽的同种异体骨髓的排斥 受到致命辐射的动物。 CTL对骨髓移植物的排斥反应 特异性针对骨髓细胞表达的 MHC 基因产物 与各个克隆的细胞毒性特异性相关。 由于分离的宿主 CTL 可能会排斥供体骨髓移植物，因此对 (l) 能够抑制宿主 CTL 反应的细胞群的植入， (2)体内施用抗CD3单克隆抗体， 通过先前的工作已显示其抑制CTL功能，进行了研究。 具有特定类型抑制活性的细胞，称为否决细胞， 据报道，这可能会抑制宿主排斥反应 存在于骨髓中。 lL-2增强否决活性的能力 T 细胞耗竭后保留在骨髓中的抑制细胞群 在体外和体内进行了研究。结果发现，T的孵化 用 IL-2 去除骨髓的细胞显着增加了否决活性， 通过体外测定进行评估，并且还增强了 MHC- 的植入 不匹配，T细胞在体内耗尽骨髓，并且否决细胞发挥作用 它们通过克隆删除前体 CTL 来发挥作用。这种克隆消除 涉及前体 CTL 和否决细胞的参与。在进一步 T 细胞耗尽的同种异体骨髓、宿主小鼠的植入研究 用抗CD3单克隆抗体进行治疗。明显增强 观察到植入；这种对植入的影响是持久的并且是由于 抑制宿主 T 细胞功能并释放多种 与抗 CD3 体内 T 细胞激活相关的细胞因子 抗体。