NK RECEPTOR FOR HLA CLASS I IN MARROW TRANSPLANTATION

本项目的总体目标是研究 异基因骨髓移植中自然杀伤细胞的作用 重点是它们对移植物排斥、残余 白血病和白血病复发。 我们的目标是开发一种DNA 基于分型系统的杀伤细胞抑制性受体 (KIR)NK细胞上表达，并研究如何匹配 这些受体的供体和受体将影响结果 骨髓移植 KIR是HLA I类配体 分子和一些KIR介导NK细胞的抑制信号 而另一些则是激活信号。 目前，40 已经鉴定了编码KIR的不同cDNA克隆。 的 这些项目的具体目标是：（一）确定外显子- 基因组KIR基因内含子组织和开发基因组 KIR基因区的地图。 (ii)开发一种基于PCR-DNA的 由单个KIR基因编码的KIR分型方法。 (iii)要将此类型化方法应用于一组不相关的 个体和对HLA相同的兄弟姐妹，并执行 单个KIR的家族分离分析。 新KIR基因 将通过核苷酸测序鉴定和表征 克隆基因。 (iv)目的建立一种基因特异性RT-PCR方法， 检测NK细胞上表达的单个KIR。 (v)到 确定患者及其骨髓供体的IKR基因型 并确定患者是否经历移植排斥反应， 移植物功能或白血病复发可与 没有这些临床事件的患者。 (vi)确定 KIR库的重建模式，因为它在 在移植后期间， 期 该项目应确定是否匹配KIR 同种异体骨髓移植的供体和受体之间的关系将 影响移植物排斥的风险， 白血病残留和复发。 我们将同时 调查KIR剧目的发展后， 移植期，并确定这是否影响 移植结果

The overall objective of this project is to investigate the role of natural killer (NK) cells in allogeneic marrow transplantation with emphasis on their influence on graft rejection, residual leukemia and leukemia relapse. The goal is to develop a DNA based typing system ofor the Killer Cell Inhibitory Receptors (KIR) expressed on NK cells and to investigate how matching donors and recipients for these receptors will affect the outcome of marrow transplantation. KIRs are ligands for HLA class I molecules and some KIRs mediate inhibitory signals for NK cells while others transduce activating signals. At present, 40 different cDNA clones encoding KIRs have been identified. The specific aims for the projects are: (i) To determine the exon- intron organization of genomic KIR genes and develop a genomic map for the KIR genetic region. (ii) to develop a PCR-DNA based typing method for KIRs encoded by the individual KIR genes. (iii) To apply this typing method to a panel of unrelated individuals and pairs of HLA identical siblings and perform family segragation analysis for individual KIRs. New KIR genes will be identified and characterized by neucleotide sequencing of clones genes. (iv) To develop a gene specific RT-PCR method for detection of individual KIRs expressed on NK cells. (v) To determine the IKR genotype in patients and their marrow donors and determine if patients experiencing graft-rejection, poor graft function or relapse of leukemia can be distinguished from patients without these clinical events. (vi) To determine the pattern of reconstitution of the KIR repertoire as it develops in themarrow transplant recipient during the post-transplantation period. This project should determine if matching for KIR between donors and recipients of allogeneic marrow grafts will affect the risk for graft rejection and the risk for minimal residual disease and relapse of leukemia. We will simultaneously investigate the KIR repertoire development in the post- transplantation period and determine if this influences transplant outcome.