GRAFT-VERSUS-HOST DISEASE PROPHYLAXIS IN ALLOGENIC BONE MARROW TRANSPLANTATION

同种异体骨髓移植中的移植物抗宿主病预防

• 批准号: 3962961
• 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/3962961
• 关键词: T lymphocyte; bone marrow transplantation; clone cells; complement; genotype; graft versus host disease; homologous transplantation; human tissue; immunohematology; immunotherapy; isoantibody; monoclonal antibody; neoplasm /cancer genetics; neoplasm /cancer immunology; radiation immunosuppression; suppressor T lymphocyte; surface antigens; tissue mosaicism

Efforts are being directed towards the prevention or control of graft-versus-host disease in human allogeneic bone marrow transplantation. Since such graft-versus-host disease is mediated by alloreactive T cells in the inoculated marrow, reagents and techniques have been developed to remove these T cells from the marrow inoculum and to measure the extent of that depletion. To this end, several murine monoclonal antibodies specific for antigens expressed on human T cells have been developed, three of which are cytotoxic. These antibodies have been untilized, in conjunction with other depletion techniques, for complement-mediated lysis of T cells in marrow. By a clonogenic assay now available, residual T cells in marrow following such a depletion are at a level of less than 0.01% of the total cell population. Therefore a bank of such T cell depleted and characterized marrows has been generated for use in the therapy of human malignancy. With respect to the control of alloreactive T cells mediating graft-versus-host disease, studies on the origin or generation of such alloreactivity have been undertaken in murine radiation bone marrow chimeras. It has been shown that the generation is influence by a unique interaction of T cell genotype and the T cell maturation environment. The fine specificity of human CTL has been demonstrated to be sufficient to distinguish among alpha 1 and alpha 2 domain changes of class I major histocompatibility complex molecules. Such mature alloreactive human cytotoxic T cells have been further studied with respect to cell surface molecules utilized in their interactions with target cells as the basis for therapeutic interventions with the intent of preventing tissue damage mediated by such alloreactive cytotoxic T cells. This in vitro generated information has been applied to bone marrow transplantation models in monkey and swine. Utilizing T cell depleted marrow, extended solid organ allograft survival (without exogoneous immunosuppression), but not long term tolerance induction, can be achieved in rhesus monkeys.

正在努力预防或控制 人异基因骨髓移植中的移植物抗宿主病 由于这种移植物抗宿主病是由同种异体反应性T细胞介导的， 已经开发了接种的骨髓、试剂和技术， 从骨髓接种物中取出这些T细胞， 这种损耗。 为此，几种鼠单克隆抗体特异性 已经开发了用于在人T细胞上表达的抗原的方法，其中三种， 有细胞毒性。 这些抗体已被利用，与 其他消耗技术，用于补体介导的T细胞裂解， 骨髓 通过现在可用的克隆形成分析，骨髓中残留的T细胞 在这种消耗之后， 细胞群 因此，这样的T细胞库被耗尽， 已经产生了特征化的骨髓，用于治疗人类 恶性肿瘤 关于同种异体反应性T细胞介导的免疫调节， 移植物抗宿主病的起源或产生的研究 同种异体反应性已在小鼠辐射骨髓中进行 嵌合体 它已被证明是由一个独特的一代的影响， T细胞基因型和T细胞成熟环境的相互作用。 的 已经证明人CTL的良好特异性足以 区分I类主要的α 1和α 2结构域变化 组织相容性复合物分子。 这种成熟的同种异体反应性人类 细胞毒性T细胞已经进一步研究了细胞表面 在与靶细胞的相互作用中利用的分子作为 旨在预防组织损伤的治疗干预 由这种同种异体反应性细胞毒性T细胞介导。 这在体外产生 信息已应用于骨髓移植模型， 猴子和猪 利用T细胞耗尽的骨髓，扩展实体器官 同种异体移植物存活（无外源性免疫抑制），但时间不长 术语耐受性诱导，可以在恒河猴中实现。