异基因造血干细胞移植中NK细胞的作用

摘要异基因造血干细胞移植后，供者细胞可产生强大而持久的免疫治疗功效，其中异源反应性NK细胞活性是T细胞异源反应活性以外的，具有显著抗肿瘤／白血病活性的自然免疫现象，并逐渐受到人们的重视。已证实，NK细胞通过其受体与靶细胞MHC分子特异性的识别机制参与移植物抗白血病（GVL）作用并影响移植物抗宿主病（GVHD）的发生。异基因造血干细胞移植后异源反应性NK细胞输注已从动物实验逐渐应用于临床。本文就NK细胞异源反应性及其在异基因造血干细胞移植中的作用进行综述。     

异基因造血干细胞移植中杀伤细胞抑制性受体(KIR)在GVHD和GVL 发生中的作用

杀伤细胞抑制性受体(KIR)属于免疫球蛋白超家族成员Ⅰ型跨膜蛋白分子，主要表达于人NK细胞和某些T淋巴细胞。它们的配体为HLA Ⅰ类分子。当KIR所识别的MHC配体缺失时，即表现为对靶细胞的杀伤作用(所谓丢失自我“missing-self”机制)。已证实，)NK细胞和T细胞的KIR分子与靶细胞的MHC分子特异性的识别机制参与移植物抗宿主病(GVHD)的发生并且影响移植物抗白血病(GVL)作用。KIR的存在可能是免疫活性细胞不攻击自身组织的主要机制。KIR基因家族及其配体HLA-C分子均具有基因多态性，因此在HLA相合和不全相合的异基因造血干细胞移植中，供受者KIR基因表达的差异在一定程度上影响移植效果。本文主要就KIR如何影响异基因造血干细胞移植后GVHD和GVL进行综述。     

激活型KIR基因家族在allo-HSCT中的研究进展

杀伤细胞免疫球蛋白样受体(killer cell immunoglobulinlike receptor,KIR)是表达于自然杀伤细胞(nature killer cell,NK)及部分T细胞表面的一类受体.NK细胞的活化依赖于KIR介导的激活信号与抑制信号之间的平衡,当抑制型信号为主时,NK细胞就处于未活化状态,反之,则发生活化.在异基因造血干细胞移植(allogenic hematopoietic stem cell transplantation,allo-HSCT)中,当抑制型KIR配体缺失时将介导NK细胞的异源反应活性,从而起到移植物抗白血病(GVL)效应.近年来有研究表明,某些特定激活型KIR表达能够降低移植后移植物抗宿主病(GvHD)发生率[1]、复发率[2]以及感染率[3]等,提高了患者的生存率.     

NK细胞异源活性与异基因造血干细胞移植

异基因造血干细胞移植后(GVHD的发病与诸多因素有关,供受者间NK细胞表面受体-配体错配产生的具有异源活性的供者NK细胞町以减少aGVHD发生.提高GVL效应和植入率.供者NK细胞异源性活化与供受者杀伤细胞免疫球蛋白样受体(killer immunoglobulin like receptor,KIR)的相配有关.国内外诸多移植中心对此进行了研究,在各种类型的移植中,NK细胞异源活性对移植预后有利有弊.这主要与移植物是否去除T淋巴细胞.以及分析采用的错配模式有关.     

杀伤细胞免疫球蛋白样受体对造血干细胞移植的影响

自然杀伤(NK)细胞表面的杀伤细胞免疫球蛋白样受体(KIR),可通过与人类白细胞抗原(HLA)相互作用,影响NK细胞活性,进而影响异基因造血干细胞移植(allo-HSCT)的预后.在去T淋巴细胞allo-HSCT中,KIR/HLA错配的异源反应性NK细胞,在抗急性髓细胞白血病(AML)中发挥了重要作用;而未去T淋巴细胞allo-HSCT中,KIR/HLA错配对患者预后影响迥异.研究者提出,在自体造血干细胞移植(auto-HSCT)中也存在移植物抗白血病(GVL)效应,并且患者存在不同KIR对移植预后影响不同.笔者拟就KIR/HLA错配在造血干细胞移植中作用的研究进展进行综述.     

KIR与异基因造血干细胞移植中的移植物抗宿主病

异基因造血干细胞移植后移植物抗宿主病(GVHD)的发生、发展、治疗一直是移植领域不懈的研究目标.自从Ruggeri等人证实体外去除T细胞的单倍体造血干细胞移植模式下同种反应性NK细胞可预防GVHD、发挥移植物抗自血病(GVL)、促进植入的特点,同种反应性NK细胞为GVHD的研究开辟了新的研究领域.但杀伤免疫球蛋白受体(KIR)只是预测同种反应性NK细胞的一方面,并不代表同种反应性NK细胞的全部.随后关于KIR与造血干细胞移植预后的文章接踵而至,不同的移植中心结论不尽相同,分析原因可能与移植模式、移植物中T细胞参与、KIR重建规律不同有关.     

自然杀伤细胞在急性髓系白血病中的临床应用

自然杀伤(NK)细胞表达许多活化或抑制性受体,这些受体与主要组织相容性复合物分子结合,从而调节免疫反应,赋予NK细胞识别靶细胞的能力.NK细胞介导的细胞毒性反应是由细胞表面抑制性或激活性受体产生信号来调节的.异基因造血干细胞移植中,供受者之间杀伤细胞免疫球蛋白样受体-配体错配引发的异体反应性NK细胞活性可以防止白血病细胞复发.本文主要阐述NK细胞的细胞毒性、其介导的抗白血病效应,以及同种异体NK细胞输注治疗急性髓系白血病的临床应用前景.     

异基因活化的NK细胞与HLA全相合同胞造血干细胞移植预后的关系

最新的研究表明,在HLA全相合同胞造血干细胞移植中,当受者的细胞表面缺乏供者NK细胞抑制型受体的配体时,供者来源的NK细胞同样会发生异基因活化,通过特异性杀伤受体抗原呈递细胞达到阻止GVHD启动的目的,主动攻击受者淋巴细胞促进供者细胞植入,识别和攻击受者白血病细胞以降低移植后白血病复发率,从而改善HLA全相合同胞造血干细胞移植患者预后,同时活化型受体亦会对患者的预后产生影响。本文就抑制性和活化性杀伤细胞免疫球蛋白样受体（KIR）对HLA全相合同胞造血干细胞移植预后影响的研究进展作一综述：     

次要组织相容性抗原在介导GVL与GVHD分离中的作用及临床应用研究进展

在异基因造血干细胞移植中,次要组织相容性抗原(mHags)介导的异源性免疫反应在移植物抗宿主病(GVHD)和移植物抗白血病(GVL)中起重要作用.局限性表达于造血细胞起源细胞表面的mHags可以增强GVL效应而不增加GVHD风险,其是实现GVL与GVHD效应的分离理想靶抗原.随着mHags发现数量的增多,基于mHags的免疫治疗有望成为造血干细胞移植后复发白血病治疗的新方法.本文对近年来mHags在介导GVL与GVHD分离中的作用及临床应用研究进展作一综述.     

CD158b基因转染的淋巴细胞对正常和HL-60细胞杀伤活性的实验研究

移植物抗宿主病 (GVHD)是异基因骨髓移植的严重并发症之一。杀伤细胞抑制性受体 (KIR)是目前发现表达于NK、T细胞膜上的一类受体 ,CD15 8分子是KIR家族重要成员 ,主要包括CD15 8a和CD15 8b。当它们与相应的HLA C分子结合后能传导抑制性信号 ,抑制NK、T细胞对靶细胞的杀伤作用[1] 。我们以 3对进行异基因骨髓移植的供、受者为对象 ,通过逆转录病毒的介导 ,将受者淋巴细胞的CD15 8b基因导入供者淋巴细胞 ,观察其对受者淋巴细胞及HL 6 0细胞的杀伤作用是否有影响 ,为解决GVHD提供理论和实验依据。对象和方法1　研究对象白血病患…     

Activating signals dominate inhibitory signals in CD137L/IL-15 activated natural killer cells

Natural killer (NK) cells can mediate potent antitumor effects, but factors regulating the efficiency of tumor lysis remain unclear. Studies in allogeneic stem cell transplantation highlight an important role for killer cell immunoglobulin-like receptor (KIR) mismatch in overcoming human leukocyte antigen-mediated inhibitory signals. However, other activating and inhibitory signals also modulate tumor lysis by NK cells. We used rhIL15 and artificial antigen presenting cells expressing CD137L and IL15Rα to activate and expand peripheral blood NK cells (CD137L/IL15 NK) up to 1000-fold in 3 weeks. Compared with resting NK cells, CD137L/IL15 NK cells show modest increases in KIR expression and substantial increases in NKG2D, tumor necrosis factor-related apoptosis-inducing ligand, and natural cytotoxicity receptors (NCRs: NKp30, NKp44, NKp46). Compared with resting NK cells, CD137L/IL15 NK cells mediate enhanced cytotoxicity against allogeneic and autologous tumors and KIR signaling did not substantially inhibit cytotoxicity. Rather, tumor lysis by CD137L/IL15 activated NK cells was predominantly driven by NCR signaling as blockade of NCRs dramatically diminished the lysis of a wide array of tumor targets. Furthermore, tumor lysis by CD137L/IL15 NK cells was tightly linked to NCR expression levels that peaked on day 8 to 10 after NK activation, and cytotoxicity diminished on subsequent days as NCR expression declined. We conclude that KIR mismatch is not a prerequisite for tumor killing by CD137L/IL15 NK cells and that NCR expression provides a biomarker for predicting potency of CD137L/IL15 NK cells in studies of NK cell-based immunotherapy.     

New directions in natural killer cell-based immunotherapy of human cancer

Efforts at harnessing the antitumour activity of natural killer (NK) cells have been investigated for the immunotherapy of human cancer for over two decades. Initial trials, focusing on the use of ex vivo-generated lymphokine activated killer (LAK) cells or activated NK cells, or in vivo cytokine therapy to expand and activate NK cells against autologous tumours, have yielded only modest success. Recent understanding of the means by which NK cells kill target cells through a complex set of activating and inhibitory receptors recognising corresponding ligands on tumour cells has paved the way for the design of improved strategies for NK cell-based immunotherapy. The net balance of activating and inhibitory signals through NK cell receptors determines whether an NK cell becomes activated or not. Successful therapeutic strategies should now focus on manipulating the balance in favour of activating receptor signalling. In the case of autologous cancers, such strategies may include the use of monoclonal antibodies with cytokines to better direct NK cells to their tumour targets through the process of antibody-dependent cellular cytotoxicity (ADCC) or the in vivo blocking of inhibitory interactions between NK receptors (NKRs) and ligands on tumour cells. Alternatively, allogeneic NK cells can be used whenever there is mismatching of inhibitory NK cell receptors and ligands. Finally, methods to modulate expression of NK cell receptors and their ligands on tumour cells by cytokines and other agents should be explored. In this review, the impact of NKR biology on the development of novel strategies for the use of NK cells in the treatment of human cancer is discussed.     

New directions in natural killer cell-based immunotherapy of human cancer

Efforts at harnessing the antitumour activity of natural killer (NK) cells have been investigated for the immunotherapy of human cancer for over two decades. Initial trials, focusing on the use of ex vivo-generated lymphokine activated killer (LAK) cells or activated NK cells, or in vivo cytokine therapy to expand and activate NK cells against autologous tumours, have yielded only modest success. Recent understanding of the means by which NK cells kill target cells through a complex set of activating and inhibitory receptors recognising corresponding ligands on tumour cells has paved the way for the design of improved strategies for NK cell-based immunotherapy. The net balance of activating and inhibitory signals through NK cell receptors determines whether an NK cell becomes activated or not. Successful therapeutic strategies should now focus on manipulating the balance in favour of activating receptor signalling. In the case of autologous cancers, such strategies may include the use of monoclonal antibodies with cytokines to better direct NK cells to their tumour targets through the process of antibody-dependent cellular cytotoxicity (ADCC) or the in vivo blocking of inhibitory interactions between NK receptors (NKRs) and ligands on tumour cells. Alternatively, allogeneic NK cells can be used whenever there is mismatching of inhibitory NK cell receptors and ligands. Finally, methods to modulate expression of NK cell receptors and their ligands on tumour cells by cytokines and other agents should be explored. In this review, the impact of NKR biology on the development of novel strategies for the use of NK cells in the treatment of human cancer is discussed.     

NK细胞表面受体及其研究进展

自然杀伤(NK)细胞是体内重要的免疫效应细胞,因其杀伤肿瘤细胞不受主要组织相容性复合物(MHC)限制、具有实现移植物抗白血病(GVL)效应与移植物抗宿主病(GVHD)分离等优势,在肿瘤过继免疫治疗中占有重要地位。研究表明,NK细胞受体众多,分别传递抑制性或活化性信号,两者间的平衡是决定NK细胞功能状态的关键因素,这为优化NK细胞过继免疫治疗提供了新思路。基于此,对于NK细胞受体的研究一直是近年来的研究热点。本文就人类NK细胞受体及临床研究进展作一综述。     

人NK细胞表面KIR与HLA I类抗原

KIR受体与HLA相互作用在人类遗传、免疫应答及异基因造血干细胞移植等方面发挥着重要作用.KIR能识别HLA I类抗原;KIR与HLA各自能独立遗传,HLA配型不能准确推断KIR表型;KIR的表达主要与其基因型有关,HLA对KIR表达的调节作用微乎其微,KIR的基因型可以决定其表现型.供受者间KIR受体-HLA配体不相合有利于异基因造血干细胞移植,尤其是单倍体相合造血干细胞移植,KIR受体-配体模型可以更好地提示造血干细胞移植的预后.本文就KIR与HLA在造血干细胞移植中的相互作用、KIR与HLA的遗传学基础、NK细胞表面KIR表达与HLA的关系及KIR和HLA在免疫应答中的作用作一综述.     

The role of natural killer cells in hematopoietic stem cell transplantation

Natural killer (NK) cells are important elements of innate immunity, and a large body of evidence supports the significant role of NK in immune surveillance against infections and tumors. Regulation of cytotoxic activity is mediated through activating and inhibitory receptors expressed on the cell surface. NK cells are key players of allogeneic hematopoietic stem cell transplantation (allo-SCT), and previous studies showed the beneficial effect of NK alloreactivity in prevention of relapse, especially in the setting of haploidentical SCT. Biology of human NK cells is an area of active research. Exploitation of the molecular mechanisms regulating NK maturation, tolerance to self, and NK-mediated cytotoxicity will help in the development of innovative NK cell immunotherapy methods.