NK细胞功能重建决定移植预后。KIR基因与HLA相互作用决定NK的成熟及获得功能，KIR与HLA基因多态性可影响KIR与HLA相互作用的亲和力强弱，调控NK细胞功能。申请人前期工作发现在非体外去除T细胞的单倍型相合移植体系下，供者KIR基因与患者HLA匹配程度促进移植后NK功能重建、降低白血病复发，且IL2可促进NK功能重建。本研究旨在以NK功能重建为主线，借助临床队列及动物模型，探讨供者KIR与患者HLA亲和力强弱对单倍体相合移植后NK功能重建调控：1）研究供者KIR与受者HLA亲和力强弱对单倍体相合移植后NK功能重建及其对预后的影响；2）结合前瞻性临床试验，探讨小剂量IL-2治疗对KIR与HLA亲和力及NK功能重建的影响；3）借助人源化小鼠模型，研究KIR与HLA亲和力改变对NK功能的影响。阐明NK细胞功能重建的调控机制，为建立促NK细胞重建新方法和指导单倍体移植的供者选择奠定基础。

Rapid NK-cell function reconstitution is important for the clinical outcomes of haploidentical hematopoietic stem cells transplantation (HSCT). The recognition of self-MHC class I by inhibitory Killer cell Ig-like receptors (KIR) is involved in the calibration of NK cell effector capacities during a developmental stage. To add further complexity to the KIR system, each gene shows considerable polymorphism. KIR and HLA class I genotype polymorphism predictive of varying degrees of receptor-ligand binding affinities affect NK cells function. Our previous study has demonstrated that recipient expression of ligands for KIRs enhances NK-cell function to control leukemic relapse after haploidentical HSCT, and IL2 can enhance NK-cell function recontitution. Based on the clinic haploidentical HSCT model and mouse model, the aims of this study are to explore differences in donor KIR and recipient HLA class I binding affinities affecting NK cells function reconstitution and influencing GVHD/GVL effect post haploidentical HSCT:1) the effect of different affinities of donor KIR bind cognate recipient HLA class I ligands on NK-cell function reconstitution as well as clinical outcomes post our novel unmanipulated blood and marrow haploidentical transplantation; 2) the effect of low dose of IL2 administrated early post transplantation on receptor-ligand binding affinities and NK-cell function reconstitution; 3) building up humanized mice models with the expression of human HLA through Crispr-Cas9 technique and comparing the functional change of donor NK cells after transferred into different humanized mice with different receptor-ligand binding affinities. Through clarifying the mechanism of NK cells function reconstitution under haploidentical hematopoietic stem cells transplantation, it would be helpful for us to explore the new ways to enhance NK cells function reconstitution and select the best donor for haploidentical transplantation.