PROGRAM PROJECT IN TRANSPLANTATION IMMUNOLOGY

移植免疫学项目

• 批准号: 3092189
• 负责人: John Andrew Hansen
• 金额: $ 76.69万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-09-30 至 1996-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3092189
• 关键词: bone marrow transplantation; transplantation immunology

Allogeneic marrow transplants from HLA genotypically identical siblings have become life-saving therapy for patients with various congenital and acquired diseases of the immune and hematopoietic systems. Graft-versus- host disease (GVHD), however, remains a significant cause of morbidity and mortality. Nonspecific immunosuppression developed through empirical trials has provided increasingly better GVHD control, but these agents are potentially toxic, they delay immunoreconstitution and increase risk of infection. In some cases immunosuppression administered for GVHD prophylaxis can abrogate the graft-versus-leukemia (GVL) effect that can occur following marrow allografting. The success of marrow allografts has drawn attention to the problem of donor availability, and less than 30% of patients in the United States have an HLA identical sibling, and thus many are denied the opportunity foe a potentially curative treatment for otherwise fatal disease. The development of a national registry of potential marrow donors by the National Marrow Donor Program (NMDP) has made it possible to access a centralized of more than 500,000 HLA typed volunteers. Unrelated donor transplants are becoming a reality for increasing numbers of patients. Our preliminary clinical experience, however has demonstrated that GVHD is increased in both incidence and severity in unrelated donor transplants. This may be explained by a lack of precision in HLA typing and an inability to achieve sufficient donor and recipient HLA matching. However, incompatibility for non-HLA minor histocompatibility determinants may also play a role. The objectives of this Program Project involve two strategies. The first is to apply molecular technology to HLA typing and donor matching. Improved HLA typing, however may not solve all problems related to donor selection because many patients will never find a perfectly matched donor. Successful management of these patients will depend on improving our understanding of T cell responses to alloantigen and development of more rational effective approaches to achieving tolerance. There are five projects in the Program Project application. Project 1 includes new studies aimed at uncovering polymorphic loci residing within the HLA class I region and continues studies of the polymorphism and functional significance of the nonclassical antigens. Project 2 is a study of HLA- A, B, C molecular variants and their significance in unrelated marrow- donor matching. Project 3 seeks to develop and evaluate cytotoxic agents directed against IL-2 receptors as a possible method of preventing GVHD. Project 4 studies the requirements for induction of T cell tolerance to allogeneic hematopoietic stem cells. Project 5 is a combined research project and core facility that provides administrative services, maintains a cell and DNA bank and a centralized HLA-clinical transplant data base. The research questions addressed in Project 5 is whether the microvariants defined by individual HLA class I alleles have significant effect on risk of rejection and GVHD.

来自人类白细胞抗原基因相合同胞的异基因骨髓移植 已经成为各种先天性和非先天性心脏病患者的救命疗法 免疫和造血系统的获得性疾病。移植物抗- 然而，宿主病(GVHD)仍然是发病率的重要原因 和死亡率。经验性发展的非特异性免疫抑制 试验提供了越来越好的GVHD控制，但这些药物 有潜在的毒性，它们会延迟免疫重建并增加风险 感染的可能性。在某些情况下，对移植物抗宿主病实施免疫抑制 预防可以消除移植物抗白血病(GVL)效应，这种效应可以 发生在同种异体骨髓移植后。异基因骨髓移植的成功 引起了人们对捐赠者可获得性问题的关注，而不到 在美国，30%的患者有完全相同的兄弟姐妹 因此，许多人被剥夺了获得潜在治愈方法的机会 对其他致命疾病的治疗。一个国家的发展 国家骨髓捐赠者计划潜在骨髓捐赠者登记 (NMDP)使访问超过500,000个集中式 人类白细胞抗原标型志愿者。无血缘关系的供者移植正在成为现实 以应对不断增加的病人数量。我们的初步临床经验， 然而，研究表明，移植物抗宿主病的发病率和 无血缘关系的供者移植的严重性。这可能是因为缺乏 人类白细胞抗原配型的准确性，以及无法获得足够的供体 和受体的人类白细胞抗原配型。然而，对于非人类白细胞抗原次要的不兼容 组织相容性决定因素也可能起到一定作用。的目标 本计划项目涉及两个战略。第一个是申请 分子技术在人类白细胞抗原配型和供者配型中的应用。改进的人类白细胞抗原 然而，打字可能并不能解决与捐献者选择有关的所有问题 因为许多患者永远也找不到完美匹配的捐献者。 这些患者的成功管理将取决于改善我们的 T细胞对同种异体抗原反应的了解及More的发展 实现宽容的合理、有效的方法。一共有五个 计划项目应用程序中的项目。项目1包括新的 旨在发现驻留在人类白细胞抗原内的多态基因座的研究 I类区域，并继续对多态和功能进行研究 非经典抗原的意义。项目2是对人类白细胞抗原的研究。 A、B、C分子变异及其在非血缘关系骨髓中的意义 捐献者匹配。项目3寻求开发和评估细胞毒剂 针对IL-2受体作为预防移植物抗宿主病的一种可能方法。 项目4研究诱导T细胞耐受的要求 异基因造血干细胞。项目5是一项综合研究 提供行政服务的项目和核心设施， 维护一个细胞和DNA库以及一个集中化的人类白细胞抗原临床移植 数据库。项目5中涉及的研究问题是 由单个人类白细胞抗原I类等位基因定义的微变异具有显著意义 对排斥反应和移植物抗宿主病风险的影响。