PROGRAM PROJECT IN TRANSPLANTATION IMMUNOLOGY

HLA基因型相同同胞的异基因骨髓移植 已成为各种先天性和先天性心脏病患者的救命疗法， 免疫和造血系统的后天性疾病。移植物抗 然而，宿主疾病（GVHD）仍然是发病的重要原因 and mortality.非特异性免疫抑制通过经验性 试验提供了越来越好的GVHD控制，但这些药物 具有潜在毒性，它们会延迟免疫功能，增加风险 感染在某些情况下，针对GVHD给予免疫抑制 预防可以消除移植物抗白血病（GVL）效应， 发生在骨髓移植后骨髓移植的成功 已提请注意能否获得捐助的问题， 在美国，30%的患者有HLA相同的兄弟姐妹， 因此，许多人被剥夺了一个潜在的治疗机会， 治疗其他致命疾病。制定国家 国家骨髓捐献者计划潜在骨髓捐献者登记处 （NMDP）使访问50多万个集中的 HLA分型志愿者无关捐赠者移植正在成为现实 越来越多的患者。我们初步的临床经验， 然而，已经证明GVHD的发生率和 无关供体移植的严重程度。这可能是因为缺乏 HLA分型的精确性和无法获得足够的供体 和受者HLA匹配。然而，非HLA次要的不相容性 组织相容性决定子也可能起作用。的目标 这个项目包含两个策略。一是适用 分子技术用于HLA分型和供体匹配。改进的HLA 然而，打字可能不能解决与供体选择有关的所有问题 因为很多病人永远找不到完全匹配的捐赠者 这些患者的成功管理将取决于改善我们的 了解T细胞对同种异体抗原的反应， 实现宽容的合理有效方法。有五 项目在项目应用程序中。项目1包括新 旨在揭示HLA内多态性基因座的研究 I类区域，并继续研究多态性和功能 非经典抗原的重要性。项目2是一项研究HLA- A、B、C分子变异及其在无关骨髓中的意义 供体匹配项目3旨在开发和评估细胞毒性药物 直接针对IL-2受体作为预防GVHD的可能方法。 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， 维持一个细胞和DNA库和一个集中的HLA临床移植 数据库项目5中提出的研究问题是， 由单个HLA I类等位基因定义的微变异具有显著的 对排斥反应和GVHD风险的影响。

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.