MARROW GRAFT FAILURE REJECTION IN ALLOGENEIC BONE MARROW TRANSPLANTATION

同种异体骨髓移植中的骨髓移植失败排斥

• 批准号: 3796554
• 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/3796554
• 关键词: CD3 molecule; antireceptor antibody; 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 (1) 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 IL-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. 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.

许多观察表明，宿主淋巴细胞， 特异性细胞毒性T细胞（CTL）可能在 介导同种异体骨髓移植排斥。 在鼠模型系统中， 从亚致死剂量照射的动物的脾脏中克隆CTL， 排斥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反应 在致命辐射的动物中。 CTL对骨髓移植物的排斥反应 对骨髓细胞表达的MHC基因产物具有特异性， 与单个克隆的细胞毒性特异性相关。 由于宿主CTL在分离状态下对供者骨髓移植物有排斥反应， （1）能够抑制宿主CTL的细胞群 （2）抗CD3单克隆抗体的给药， 体内，其通过先前的工作已经显示出抑制CTL功能， 研究了 具有特定类型抑制活性的细胞，称为 否决细胞可能抑制宿主的排斥反应， 据报道存在于骨髓中。 IL-2能够增强 T细胞移植后保留在骨髓中的否决抑制细胞群的活性 在体外和体内研究细胞去除。 结果发现 用IL-2孵育T细胞耗尽骨髓显著地 通过体外测定评估的增加的否决活性， 体内移植MHC不匹配的T细胞耗尽的骨髓， veto细胞通过克隆性缺失前体CTL发挥作用。 在 进一步研究T细胞耗尽的同种异体骨髓、宿主 用抗-CD3单克隆抗体处理小鼠。 明显强化 的植入;这种对植入的影响是持久的， 由于宿主T细胞功能的抑制和多种细胞因子的释放， 与抗CD3抗体体内活化T细胞相关的细胞因子 抗体的