KIR基因组合型与肾移植术后急性排斥反应关系的研究
摘要
随着肾脏移植组织配型技术不断进步,新型的免疫抑制剂及生物制剂不断开发并越来越规范应用于临床,使得肾移植后超急性(加速)排斥反应基本得以避免,同时急性排斥反应率及排斥强度也得以降低。但在相同组织配型和应用免疫抑制药物的条件下,仍有一些病人发生了急性排斥反应,急性排斥反应不仅可以引起移植肾早期失功,而且是影响移植肾长期生存的最重要因素之一。这也使得减低肾移植后急性排斥反应和延长移植物有功能生存时间成为需要解决的重大课题。除了传统的组织配型,可能还有其他的移植免疫通路发挥着作用。自然杀伤细胞(nature killer cell NK细胞)和部分效应T细胞表面免疫球蛋白样受体(killer cell immunoglobulin-like receptor,KIR)作为的HLA的配体与移植排斥反应的关系在近年来得到重视。
KIR分子属于免疫球蛋白样超家族,表达于NK和部分效应T细胞表面。KIR基因座位编码在常染色体19q13.4,呈共显性表达,共有16种KIR基因,包括14个功能基因和2个沉默基因。其编码蛋白KIR受体为跨膜糖蛋白,按其胞浆区的长短KIR分为L型和S型,L型传导抑制型信号,称抑制型KIR(inhibitory KIR);S型传导活化型信号,称活化型KIR(activatory KIR)。KIR受体可特异性识别结合HLA-Ⅰ类抗原,从而传导并调节NK细胞和部分效应性T细胞杀伤靶细胞的作用。又根据KIR受体在胞外区免疫球蛋白样结构域的数目,KIR基因编码蛋白分为KIR2D和KIR3D,KIR2D包括KIR2DL1～L5,KIR2DS1～S5;KIR3D包括KIR3DL1～L3和KIR3DS1。如抑制型受体KIR3DL1有三个免疫球蛋白样结构域和含有免疫受体酪氨酸抑制基序(immunoreceptor tyrosine-based inhibitory motif,ITIM);如活化型受体KIR3DS1,其跨膜区还含有能与特异性接头蛋白相结合的带有正电荷的残基,不含ITIM序列。抑制型KIR受体传导抑制信号产生控制NK细胞杀伤效应,活化型KIR受体则缺乏ITIM基序,导致活化信号通路形成刺激NK细胞和效应T细胞杀伤靶细胞。
一个NK细胞可以单独或同时表达多个KIR2D和KIR3D分子,也可以单独或同时表达多个活化型和抑制型受体。一般来讲,KIR2D分子的配体为HLA-Cw,而KIR3D分子的配体为HLA-A或HLA-B。与活化型KIR受体相比,抑制型KIR受体与HLA-Ⅰ类抗原结合的亲和性更强,当抑制型和活化型KIR受体识别和结合同一HLA-Ⅰ类抗原分子时,以抑制作用为主。KIR与相应HLA-Ⅰ结合后可能产生以下4种情况:①当抑制型KIR与HLA-Ⅰ结合而无活化型KIR与HLA-Ⅰ相互作用时,因抑制信号通路启动而不产生细胞溶解;②当活化型KIR与靶细胞表面的相应HLA-Ⅰ结合同时无抑制型KIR与HLA-Ⅰ的相互作用时,形成刺激信号通路,导致靶细胞溶解。③如果KIR与相应HLA-Ⅰ结合后HLA-Ⅰ-KIR抑制型及刺激型信号均被启动,当刺激型HLA-Ⅰ-KIR的相互作用强于抑制型HLA-Ⅰ-KIR的相互作用时,仍可致使NK细胞活化,靶细胞溶解。④如果KIR与相应HLA-Ⅰ结合后HLA-Ⅰ-KIR抑制型及活化型信号均被启动,当抑制型HLA-Ⅰ-KIR相互作用显著强于活化信号时,产生抑制信号通路;或者既无活化又无抑制信号,故而不发生NK细胞所致的靶细胞溶解。这见于NK细胞识别正常组织的情况。
目前,我们在临床上常规的组织配型包括HLA-A、B、DR基因分型,群体反应性抗体(Panel Reactive Antibodies,PRA)测定,补体依赖微量淋巴细胞毒(Health-Complement Dependent Cytotoxieity,CDC)实验。近年来对HLA生物学和造血干细胞移植等基础研究发现,HLA-Cw-KIR,即HLA及其配体KIR在造血干细胞移植及实体肿瘤治疗中可以形成不同的(刺激或抑制)免疫传导信号并发生不同的(排斥或耐受)免疫调节通路。
不同种族不同个体各种KIR基因的频率是不相同的,所以不同个体的KIR基因组合型也有所不同。KIR基因呈共显性表达,个体间因KIR基因组合型不同,其体内NK细胞和部分T细胞表面KIR受体类型而有所不同,所表现的免疫传导刺激信号通路也会不同。肾脏移植本身是受者接受供者的异类抗原即移植肾的过程,必然在受者体内发生一系列针对移植物的免疫反应。
在肾脏移植后早期发生的排斥反应中HLA-Ⅰ-KIR是否参与免疫应答作用是我们将探讨的问题,本研究拟在肾移植传统配型基础上,观察KIR基因在人群中的频率及基因组合型的分布,分析肾移植供受者的KIR抑制型基因组合型与急性排斥反应的关联。本论文分为以下三章。
第一章杀伤细胞免疫球蛋白样受体KIR基因的检测
目的调查尿毒症患者杀伤细胞免疫球蛋白样受体KIR基因的频率。
方法选择本移植中心55例等候肾脏移植的尿毒症患者,抽取静脉血。根据2006年11月10日IDP KIR序列数据库(www.ebi.ac.uk/ipd/kir)公布的KIR碱基编码序列(release 1.3.0),共设计23对上下游引物序列均经过BLAST软件验证,可识别16个KIR基因,包括14个功能基因和2个沉默基因。测定DNA浓度和纯度,采用聚合酶链式反应序列特异引物分型技术(polymerase chain recation-sequencesspecific primer,PCR-SSP),检测55例等候肾脏移植的尿毒症患者的KIR基因频率并与韩国人、日本人、南亚人群中的KIR基因频率进行比较。
结果55例等候肾脏移植的尿毒症患者检测出全部16个KIR基因,包括14个功能基因(2DL1、2DL2、2DL3、2DL4、2DL5、3DL1、3DL2、3DL3、2DS1、2DS2、2DS3、2DS4、2DS5、3DS1)和2个沉默基因(2DP1,3DP1)。其中,2DL4、3DL2、3DL3、3DP1基因频率1.00;2DL1、2DL3、3DL1、2DS4基因频率0.73～0.87;2DL2、2DS1、2DS2、2DS3、2DS5基因频率0.11～0.25;2DL5、3DS1、2DP1基因频率0.30～0.41。对等候肾脏移植的尿毒症患者与部分亚洲地区人群的KIR基因频率比较分析中发现,2DL4、3DL1、3DL2、3DL3、2DS4(GF 0.73～1.00)和2DL2、2DL5、2DS1、2DS3、2DS5、3DS1(GF 0.11～0.34)与韩国人、日本人、南亚人之间相差＜0.20;2DL1、2DL3、2DS2与韩国人、日本人、南亚人群之间相差≥0.2,2DL1低于日本人,2DS2低于南亚人,2DL3高于南亚人。
结论55例等候肾脏移植的尿毒症患者普遍带有KIR结构基因2DL4、3DL2、3DL3、3DP1,其次为2DL3、3DL1、2DL1、2DS4,较罕见2DP1、3DS1、2DL5及2DL2、2DS1、2DS2、2DS5、2DS3。这些患者中14个KIR功能基因与亚洲其他人群KIR基因频率接近,但是KIR基因多态性与上述不同种族之间存在分布差异。
第二章杀伤细胞免疫球蛋白样受体KIR基因组合型的分析
目的探讨人类杀伤细胞免疫球蛋白受体KIR基因组合类型的分布。
方法调查志愿者中国汉族67人,抽取静脉血。根据2006年11月10日IDP KIR序列数据库(www.ebi.ac.uk/ipd/kir)公布的KIR碱基编码序列(release1.3.0),共设计23对上下游引物序列,经BLAST软件验证可识别16个KIR基因及等位基因,测定DNA浓度和纯度,采用聚合酶链式反应序列特异引物分型技术(PCR-SSP)调查和分析67例中国人的KIR基因和基因组合型频率。
结果本文中国人群检测出16个KIR基因,包括14个功能基因(2DL1、2DL2、2DL3、2DL4、2DL5、3DL1、3DL2、3DL3、2DS1、2DS2、2DS3、2DS4、2DS5、3DS1)和2个沉默基因(2DP1,3DP1)。由14个KIR功能基因组成的KIR基因组合型供检测出25个,其中仅KIR-2DL1-2DL3-2DL4-3DL1-3DL2-3DL3-2DS4基因组合型的分布频率达到0.373,而其余24个KIR基因组合型频率均≤0.09。本文检测的中国人群25个KIR基因组合型与已报道的日本人群、韩国人群和高加索人群中KIR基因组合型累计有56个KIR基因组合型。比较4个人群间KIR基因组合型,有5种基因组合型为4个人群所共有,4个人群间KIR基因组合型共享率为8.93%(5/56)。此外,有3种基因组合型为本文中国人群、韩国人群和高加索人群所共有,在日本人群中未见报道,本文中国人群、韩国人群和高加索人群KIR基因组合型共享率为为5.36%(3/56);有1种基因组合型为本文中国人群和高加索人群所共有,本文中国人群和高加索人群间KIR基因组合型共享率为1.79%(1/56)。16种基因组合型为本文中国人群所独有28.58%(16/56);2种基因组合型为日本人群所独有3.57%(2/56);9种基因组合型为韩国人群所独有16.07%(9/56);16种基因组合型为高加索人群所独有28.58%(16/56);
结论在本文检测到国人25个KIR基因组合型中,仅有以传导抑制信号为主的基因组合型KIR-2DL1-2DL3-2DL4-3DL1-3DL2-3DL3-2DS4的分布频率较高,其余24种基因组合型分布频率较低,并且基因组合型KIR-2DL1-2DL3-2DL4-3DL1-3DL2-3DL3-2DS4在四个民族和地区人群中均分布最高。
第三章抑制型KIR基因组合型与肾移植急性排斥反应的关系
目的:探讨抑制型KIR基因组合型(AA类型)传导通路与尸体肾移植受者发生急性排斥反应(AR)的关系。
方法:抽取本移植中心24对供受者静脉血。根据2006年11月10日IDP KIR序列数据库(www.ebi.ac.uk/ipd/kir)公布的KIR碱基编码序列(release 1.3.0),共设计23对上下游引物序列,经BLAST软件验证可识别16个KIR基因,包括14个功能基因(2DL1、2DL2、2DL3、2DL4、2DL5、3DL1、3DL2、3DL3、2DS1、2DS2、2DS3、2DS4、2DS5、3DS1)和2个沉默基因(2DP1,3DP1)。测定DNA浓度和纯度。应用PCR-SSP方法检测24对肾脏移植供受者的KIR基因组合型,参照Marsh等在WHO-KIR命名委员会2002年发表的报告,将14个KIR功能基因的组合界定为抑制型KIR(L-KIR)基因组合型和非抑制型KIR(non-L-KIR)基因组合型。抑制型基因组合型是由多个抑制性KIR(L-KIR)基因(2DL1,2DL3,2DL4,3DL1,3DL2,3DL3)和单个激活性(S-KIR)基因(2DS4)组成的KIR基因组合型编为AA类型。而非抑制型基因组合的两种类型(BB,AB)为由多个L-KIR基因(2DL1,2DL3,2DL4,3DL1,3DL2,3DL3)与除2DS4外的S-KIR基因(2DS1,KIR-2DS2,KIR-2DS3,KIR-2DS5,KIR-3DS1)组成的KIR基因组合型编为BB类型;由多个L-KIR基因(2DL1,2DL3,2DL4,3DL1,3DL2,3DL3)和含有2DL4的多个S-KIR基因(2DS1,2DS2,2DS3,2SD4,2DS5,3DS1)组成的KIR基因组合型编为AB类型。
结果:24对供受者中AA类型基因组合型的供者9例,受者10例;BB类型基因组合型供者为3例,受者4例,AB类型基因组合型供者12例,受者10例。AA类型基因组合型受者术后急性排斥反应的发生率10%(1/10);BB和AB类型基因组合型的受者术后急性排斥反应的发生率64.29%(9/14),两组急性排斥反应的发生率呈显著差异(P＜0.05)。供者AA类型基因组合型受者术后急性排斥反应的发生率11.11%(1/9),供者BB和AB类型基因组合型的受者术后急性排斥反应的发生率60%(9/15)(P＜0.05)。供受者均AA/AA基因组合型配型的受者移植后急性排斥反应的发生率为0%(0/4);而供受者不是AA/AA基因组合型配型的受者术后急性排斥反应的发生率为50%(10/20)(P＞0.05)。
结论:AA类型基因组合型受者肾移植术后急性排斥反应的发生率低,对BB或AB类型基因组合型受者选择AA类型基因组合型的供肾能够降低急性排斥反应的发生率。提示抑制型基因组合型AA类型在肾移植早期可能主要传导抑制信号通路为主。
With the progress of the tissue matching technique in kidney transplantation, new immunosuppressive agent and biological agent used to clinic become nomal, which keep the supper-acute rejection(AR) away on the whole,meanwhile,the rate and strength of the AR is cut down.But in the same condition of tissue matching and immunosuppressive agent used,some patient occur AR.The AR not only occur graft failure in earlier period,but the one of the most important factor of the graft long term survival.This make to reduce AR after kidney transplantation and to prolong the live time of the graft become a important topic.beside the tissue matching,there may be orther transplantation immunity access play a role.The relationship of killer cell immunoglobulin-like receptor which is the ligand of the HLA in the surface of nature killer cell and part of effector T cells with transplantation AR have much attention.
KIR molecule belong to immuneglobulin superfamilly,express to the surface of the NK cell and part effector T cells.KIR Genes coding for them are found on chromosome 19q13.4,express codominance,owned 16 KIR gene,cotents 14function genes and 2silent genes.Its encoding proteinum KIR receptor is transmembrane glycoprotein,according to the side of cytoplasmic domain,KIRdivide to L-type and S-type,L-type transmit inhibitory signal,named inhibitory KIR;S-type transmit activate signal,named activatory KIR.KIR receptor can recognite and blind HLA-Ⅰantigen specificity,so transmit and regulate NK cell and part effector T cells kill target cell.According to the numbers of the immunoglobulin like domain extracellular region,KIR gene cord protein individe as KIR2D and KIR3D,KIR2D consist of KIR2DL1～L5,KIR2DS1～S5;KIR3D consist of KIR3DL1～L3 and KIR3DS1。
For example:inhibitory receptor KIR3DL1 have three immunoglobulin like domain and immunoreceptor tyrosine-based inhibitory motif(ITIM) activatory receptor KIR3DS1,its transmembrane domain has with positive charge residue that can bind specificity junct protein,no ITIM.inhibitory KIR receptor transmit inhibitor signal control NK cell kill target cell,activatory KIR receptor lack of ITIM,let activatory signal access form active NKcell and effective T cell kill target cell.
A NK cell may express multitude KIR3D and KIR3D molecule alone or at equal pace,likewise,can express multitude activatory or inhibitory receptor.generally,the ligand of KIR2D is HLA-Cw,and the ligand of KIR3D is HLA-A and HLA-B4. compared activatory receptor,inhibitory receptor have more closed affinity with HLA-Ⅰ,when activatory or inhibitory receptor recognite and bind the same HLA-Ⅰantigen,inhibitory effect play the main role.KIR bind corresponding HLA-Ⅰmay hame four results followed:1、When inhibitory KIR bind HLA-Ⅰand there has no activatory KIR bind it,cell isn't dissolve because inhibitory signal access was done;2、When activatory KIR bind corresponding HLA-Ⅰand there has no inhibitory KIR bind it,form activate signal,lead cell dissolve.3、If activatory or inhibitory receptor both bind HLA-Ⅰ,both signal access is make done,when activatory signal play the main role,NK cell still actived,lead target cell dissolve.4、If activatory or inhibitory receptor both bind HLA-Ⅰ,both signal access is make done,when inhibitory signal play the main role,or both signal access don't play,NK cell do not make effect.this is NK cell recognice nomal tissue.
At present,in clinic,tissue matching contains HLA-A、B、DR genotyping,PRA and CDC.Recent years,some foundation study of HLA biology and hemopoietic stem cell transplantation finding that HLA-Cw-KIR,HLA and its ligand KIR form differ immunity transmit signal and lead differ immunity regulate access in hemopoietic stem cell transplantation and tumor treatment.
The frequencies of KIR gene in different race and different individual is different, so the KIR genotype in individual may different.KIR gene is express codominanced, KIR genotype differ between individual,so in vivo NK cell and part effect T cell sufface KIR receptor type may differed,lead immunity transmit signal may deffered.Kidney transplantation is recipient accept donor's antigent,a series of immunity reaction aim to graft occurd necessarily.
Whether or not HLA-Ⅰ-KIR play the role at immune response in the AR on earlier period after kidney transplantation,this research review the frequencies that KIR genes in population and the distribution of its genotypes,analysis the correlation that inhibitory genotypes of kidney donor-recipient pair with AR.This article contains three chapters followed:
Chapter one The detection of killer cell immunoglobulin-like receptor KIR genes
Objective To investigate the KIR gene frenquencies of killer cell immunoglobulin-like receptor of uremia patients.
Methods Uremia patients were chosen to drawn venous blood According the KIR basic radical coded sequence that publication by IDP KIR sequence library(www.ebi.ac.uk/ipd/kir) on November 10,2006.Twenty-three pairs of primers were designed,whole were verification by BLAST software,which can recognize 16 KIR genes,contains 14 functional genes and 2 silent genes.In our unit,55 uremia patients who waiting for kidney transplantation.Analysis by polymerase chain recation-sequences specific primer,PCR-SSP,work out the KIR gene frenquencies of 55 uremia patients,compared with Korean,Japanese,Southern Asian.
Results Sixteen genes were observed in uremia patients,contains 14 functional genes(2DL1、2DL2、2DL3、2DL4、2DL5、3DL1、3DL2、3DL3、2DS1、2DS2、2DS3、2DS4、2DS5、3DS1)and 2 silent genes(2DP1,3DP1).
The frequencies(GF)of 2DL4,3DL2,3DL3 and 3DP1 are 1.00;2DL1,2DL3, 3DL1 and 2DS4 are 0.73～0.87;2DL2,2DS1,2DS2,2DS3 and 2DS5 are 0.11～ 0.25;2DL5,3DS1 and 2DP1 are 0.30～0.41.Compared the frequencies of uremia patients(GF 0.73～1.00 in KIR-2DL4,3DL1,3DL2,3DL3,2DS4) &(GF 0.11～0.34 in KIR-2DL2,2DL5,2DS1,2DS3,2DS5,3DS1)with Korean,Japanese, Southern Asian subjects,the difference were less than 0.20.In addition,the frequencies of KIR-2DL1 in uremia patients was lower than Japanese,2DS2 was lower than Southern Asian,and 2DL3 was higher than Southern Asain.
Conclusions All 16 known genes observed in uremia patients indicated that the KIR genes are polymorphic.The most frequent genes were 2DL4,3DL2,3DL3 and 3DP1;followed by 2DL1,2DL3,3DL1 and 2DS4;rare of 2DL2,2DS1, 2DS2,2DS3 and 2DS5.This study shows that there is a high concordance but variability in the frequent distributions of KIR gene among the uremia patients and Asian populations.
Chapter two Analysis of killer cell immunoglobulin-like receptor KIR genotypes
Objective To investigate the killer cell immunoglobulin-like receptor KIR genetypes distribution of population
Methods DNA samples from 67 randomly unrelated individuals in Chinese Han population were genotyped with PCR-SSP method and a comparison of frequencies of KIR genes were done with other populations.According the KIR basic radical coded sequence that publication by IDP KIR sequence library (www.ebi.ac.uk/ipd/kir) on November 10,2006.Twenty-three pairs of primers were designed,whole were verification by BLAST software,which can recognize 16 KIR genes and alliles.
Results 16 KIR genes were found in Chinese Han individual in this study, contains 14 functional genes(2DL1、2DL2、2DL3、2DL4、2DL5、3DL1、3DL2、3DL3、2DS1、2DS2、2DS3、2DS4、2DS5、3DS1)and 2 silent genes(2DP1,3DP1). There were 25 genetypes constitution by 14 functional genes were detected.among them the most frequent one was KIR-2DL1-2DL3-2DL4-3DL1-3DL2-3DL3- 2DS4(0.373),the other 24 were≤0.09.Comparing the Chinese Han KIR combinations with these of Japanese,Korean,Caucasians,there are 56 KIR genotypes summary. Analysis the KIR genotypes in the four populations,they are share 5 KIR genotypes, 8.93%of the KIR combinations were detected in all these populations;5.36%were detected in Chinese,Koreans and Caucasians;1.79%were only found in Chinese and Caucasians;In this study,16 kinds of new gene combinations were identified (28.58%).2 kinds of genotypes were only found in Japanese(3.57%);9 kinds of genotypes were only found in Korean(16.07%);and 16 kinds of genotypes were only found in Caucasians(28.58%).
Conclusions This study shows that Among 25 KIR genotypes in the 67 Chinese Han,only the distribution frequency of KIR-2DL1-2DL3-2DL4-3DL1-3DL2-3DL3-2DS4 was 0.373(4%),which is an inhibitable signal transduction pathway.We found one kind of KIR combination(KIR-2DLl-2DL3-2DL4-3DL1-3DL2-3DL3-2DS4) is the most frequent in all these populations(Chinese,Japanese, Koreans and Caucasians).
Chapter three Association between inhibitory KIR genotype and acute rejection after kidney transplantation
Objective To investigate the effect of inhibitory KIR genotypes(L-KIR,AA) on acute rejection(AR) after cadaveric kidney transplantation.
Mothods DNA samples from 24 donor-recipient pair were genotyped with PCR-SSP method and a comparison of frequencies of KIR genes were done with other populations.According the KIR basic radical coded sequence that publication by IDP KIR sequence library(www.ebi.ac.uk/ipd/kir) on November 10,2006. Twenty-three pairs of primers were designed,whole were verification by BLAST software,which can recognize 16 KIR that contains 14 functional genes(2DL1、2DL2、2DL3、2DL4、2DL5、3DL1、3DL2、3DL3、2DS1、2DS2、2DS3、2DS4、2DS5、3DS1)and 2 silent genes(2DP1,3DP1),reference to the report that make by Marsh in WHO-KIR Nomenklatur Kommission in 2002.It identify the 14 functional genes to inhibition genotype and non inhibition genotypes,inhibition genotype consist by some inhibitory KIR genes(2DL1,2DL3,2DL4,3DL1,3DL2,3DL3) and a activatory KIR gene(2DS4),named group AA.non inhibition genotypes content two group,group BB and AB.BB consist by some inhibitory KIR genes (2DL1,2DL3,2DL4,3DL1,3DL2,3DL3) and some activatory KIR genes(2DS1, 2DS2,2DS3,2DS5,3DS1)(no 2DS4);AB consist by some inhibitory KIR genes (2DL1,2DL3,2DL4,3DL1,3DL2,3DL3) and some activatory KIR genes(2DS1, 2DS2,2DS3,2SD4,2DS5,3DS1)(content 2DS4).
RESULTS:Of the 24 pairs,AA KIR genotype was found in 9 donors and 10 recipients;BB KIR genotype was found in 3 donors and 4 recipients;AB KIR genotype was observed in 12 donors and 10 recipients.AR occurred in 10%(1/10) of the recipients with AA KIR genotype and in 64.29%(9/14) of the recipients with BB & AB KIR genotype.The difference between the two groups was significant (P＜0.05).11.11%(1/9) of the donors with AA KIR genotype had AR while 60% (9/15) of the donors with BB & AB KIR genotypes suffered AR,with significant difference between the two groups(P＜0.05).0%(0/4) of the donors/recipients with AA/AA match had AR while 50%(10/20) of the donors/recipients with non-AA/AA match suffered AR,without significant difference(P＞0.05).
CONCLUSIONS:Recipients with AA KIR genotype tend to have a lower incidence of AR,while for recipients with BB & AB KIR genotypes,choice of a graft with AA KIR genotype may reduce the incidence of AR.These may be due to the possible mechanism that AA KIR genotype was characterized by inhibitory conducting signals after kidney transplantation early.
KIR分子属于免疫球蛋白样超家族,表达于NK和部分效应T细胞表面。KIR基因座位编码在常染色体19q13.4,呈共显性表达,共有16种KIR基因,包括14个功能基因和2个沉默基因。其编码蛋白KIR受体为跨膜糖蛋白,按其胞浆区的长短KIR分为L型和S型,L型传导抑制型信号,称抑制型KIR(inhibitory KIR);S型传导活化型信号,称活化型KIR(activatory KIR)。KIR受体可特异性识别结合HLA-Ⅰ类抗原,从而传导并调节NK细胞和部分效应性T细胞杀伤靶细胞的作用。又根据KIR受体在胞外区免疫球蛋白样结构域的数目,KIR基因编码蛋白分为KIR2D和KIR3D,KIR2D包括KIR2DL1～L5,KIR2DS1～S5;KIR3D包括KIR3DL1～L3和KIR3DS1。如抑制型受体KIR3DL1有三个免疫球蛋白样结构域和含有免疫受体酪氨酸抑制基序(immunoreceptor tyrosine-based inhibitory motif,ITIM);如活化型受体KIR3DS1,其跨膜区还含有能与特异性接头蛋白相结合的带有正电荷的残基,不含ITIM序列。抑制型KIR受体传导抑制信号产生控制NK细胞杀伤效应,活化型KIR受体则缺乏ITIM基序,导致活化信号通路形成刺激NK细胞和效应T细胞杀伤靶细胞。
一个NK细胞可以单独或同时表达多个KIR2D和KIR3D分子,也可以单独或同时表达多个活化型和抑制型受体。一般来讲,KIR2D分子的配体为HLA-Cw,而KIR3D分子的配体为HLA-A或HLA-B。与活化型KIR受体相比,抑制型KIR受体与HLA-Ⅰ类抗原结合的亲和性更强,当抑制型和活化型KIR受体识别和结合同一HLA-Ⅰ类抗原分子时,以抑制作用为主。KIR与相应HLA-Ⅰ结合后可能产生以下4种情况:①当抑制型KIR与HLA-Ⅰ结合而无活化型KIR与HLA-Ⅰ相互作用时,因抑制信号通路启动而不产生细胞溶解;②当活化型KIR与靶细胞表面的相应HLA-Ⅰ结合同时无抑制型KIR与HLA-Ⅰ的相互作用时,形成刺激信号通路,导致靶细胞溶解。③如果KIR与相应HLA-Ⅰ结合后HLA-Ⅰ-KIR抑制型及刺激型信号均被启动,当刺激型HLA-Ⅰ-KIR的相互作用强于抑制型HLA-Ⅰ-KIR的相互作用时,仍可致使NK细胞活化,靶细胞溶解。④如果KIR与相应HLA-Ⅰ结合后HLA-Ⅰ-KIR抑制型及活化型信号均被启动,当抑制型HLA-Ⅰ-KIR相互作用显著强于活化信号时,产生抑制信号通路;或者既无活化又无抑制信号,故而不发生NK细胞所致的靶细胞溶解。这见于NK细胞识别正常组织的情况。
目前,我们在临床上常规的组织配型包括HLA-A、B、DR基因分型,群体反应性抗体(Panel Reactive Antibodies,PRA)测定,补体依赖微量淋巴细胞毒(Health-Complement Dependent Cytotoxieity,CDC)实验。近年来对HLA生物学和造血干细胞移植等基础研究发现,HLA-Cw-KIR,即HLA及其配体KIR在造血干细胞移植及实体肿瘤治疗中可以形成不同的(刺激或抑制)免疫传导信号并发生不同的(排斥或耐受)免疫调节通路。
不同种族不同个体各种KIR基因的频率是不相同的,所以不同个体的KIR基因组合型也有所不同。KIR基因呈共显性表达,个体间因KIR基因组合型不同,其体内NK细胞和部分T细胞表面KIR受体类型而有所不同,所表现的免疫传导刺激信号通路也会不同。肾脏移植本身是受者接受供者的异类抗原即移植肾的过程,必然在受者体内发生一系列针对移植物的免疫反应。
在肾脏移植后早期发生的排斥反应中HLA-Ⅰ-KIR是否参与免疫应答作用是我们将探讨的问题,本研究拟在肾移植传统配型基础上,观察KIR基因在人群中的频率及基因组合型的分布,分析肾移植供受者的KIR抑制型基因组合型与急性排斥反应的关联。本论文分为以下三章。
第一章杀伤细胞免疫球蛋白样受体KIR基因的检测
目的调查尿毒症患者杀伤细胞免疫球蛋白样受体KIR基因的频率。
方法选择本移植中心55例等候肾脏移植的尿毒症患者,抽取静脉血。根据2006年11月10日IDP KIR序列数据库(www.ebi.ac.uk/ipd/kir)公布的KIR碱基编码序列(release 1.3.0),共设计23对上下游引物序列均经过BLAST软件验证,可识别16个KIR基因,包括14个功能基因和2个沉默基因。测定DNA浓度和纯度,采用聚合酶链式反应序列特异引物分型技术(polymerase chain recation-sequencesspecific primer,PCR-SSP),检测55例等候肾脏移植的尿毒症患者的KIR基因频率并与韩国人、日本人、南亚人群中的KIR基因频率进行比较。
结果55例等候肾脏移植的尿毒症患者检测出全部16个KIR基因,包括14个功能基因(2DL1、2DL2、2DL3、2DL4、2DL5、3DL1、3DL2、3DL3、2DS1、2DS2、2DS3、2DS4、2DS5、3DS1)和2个沉默基因(2DP1,3DP1)。其中,2DL4、3DL2、3DL3、3DP1基因频率1.00;2DL1、2DL3、3DL1、2DS4基因频率0.73～0.87;2DL2、2DS1、2DS2、2DS3、2DS5基因频率0.11～0.25;2DL5、3DS1、2DP1基因频率0.30～0.41。对等候肾脏移植的尿毒症患者与部分亚洲地区人群的KIR基因频率比较分析中发现,2DL4、3DL1、3DL2、3DL3、2DS4(GF 0.73～1.00)和2DL2、2DL5、2DS1、2DS3、2DS5、3DS1(GF 0.11～0.34)与韩国人、日本人、南亚人之间相差＜0.20;2DL1、2DL3、2DS2与韩国人、日本人、南亚人群之间相差≥0.2,2DL1低于日本人,2DS2低于南亚人,2DL3高于南亚人。
结论55例等候肾脏移植的尿毒症患者普遍带有KIR结构基因2DL4、3DL2、3DL3、3DP1,其次为2DL3、3DL1、2DL1、2DS4,较罕见2DP1、3DS1、2DL5及2DL2、2DS1、2DS2、2DS5、2DS3。这些患者中14个KIR功能基因与亚洲其他人群KIR基因频率接近,但是KIR基因多态性与上述不同种族之间存在分布差异。
第二章杀伤细胞免疫球蛋白样受体KIR基因组合型的分析
目的探讨人类杀伤细胞免疫球蛋白受体KIR基因组合类型的分布。
方法调查志愿者中国汉族67人,抽取静脉血。根据2006年11月10日IDP KIR序列数据库(www.ebi.ac.uk/ipd/kir)公布的KIR碱基编码序列(release1.3.0),共设计23对上下游引物序列,经BLAST软件验证可识别16个KIR基因及等位基因,测定DNA浓度和纯度,采用聚合酶链式反应序列特异引物分型技术(PCR-SSP)调查和分析67例中国人的KIR基因和基因组合型频率。
结果本文中国人群检测出16个KIR基因,包括14个功能基因(2DL1、2DL2、2DL3、2DL4、2DL5、3DL1、3DL2、3DL3、2DS1、2DS2、2DS3、2DS4、2DS5、3DS1)和2个沉默基因(2DP1,3DP1)。由14个KIR功能基因组成的KIR基因组合型供检测出25个,其中仅KIR-2DL1-2DL3-2DL4-3DL1-3DL2-3DL3-2DS4基因组合型的分布频率达到0.373,而其余24个KIR基因组合型频率均≤0.09。本文检测的中国人群25个KIR基因组合型与已报道的日本人群、韩国人群和高加索人群中KIR基因组合型累计有56个KIR基因组合型。比较4个人群间KIR基因组合型,有5种基因组合型为4个人群所共有,4个人群间KIR基因组合型共享率为8.93%(5/56)。此外,有3种基因组合型为本文中国人群、韩国人群和高加索人群所共有,在日本人群中未见报道,本文中国人群、韩国人群和高加索人群KIR基因组合型共享率为为5.36%(3/56);有1种基因组合型为本文中国人群和高加索人群所共有,本文中国人群和高加索人群间KIR基因组合型共享率为1.79%(1/56)。16种基因组合型为本文中国人群所独有28.58%(16/56);2种基因组合型为日本人群所独有3.57%(2/56);9种基因组合型为韩国人群所独有16.07%(9/56);16种基因组合型为高加索人群所独有28.58%(16/56);
结论在本文检测到国人25个KIR基因组合型中,仅有以传导抑制信号为主的基因组合型KIR-2DL1-2DL3-2DL4-3DL1-3DL2-3DL3-2DS4的分布频率较高,其余24种基因组合型分布频率较低,并且基因组合型KIR-2DL1-2DL3-2DL4-3DL1-3DL2-3DL3-2DS4在四个民族和地区人群中均分布最高。
第三章抑制型KIR基因组合型与肾移植急性排斥反应的关系
目的:探讨抑制型KIR基因组合型(AA类型)传导通路与尸体肾移植受者发生急性排斥反应(AR)的关系。
方法:抽取本移植中心24对供受者静脉血。根据2006年11月10日IDP KIR序列数据库(www.ebi.ac.uk/ipd/kir)公布的KIR碱基编码序列(release 1.3.0),共设计23对上下游引物序列,经BLAST软件验证可识别16个KIR基因,包括14个功能基因(2DL1、2DL2、2DL3、2DL4、2DL5、3DL1、3DL2、3DL3、2DS1、2DS2、2DS3、2DS4、2DS5、3DS1)和2个沉默基因(2DP1,3DP1)。测定DNA浓度和纯度。应用PCR-SSP方法检测24对肾脏移植供受者的KIR基因组合型,参照Marsh等在WHO-KIR命名委员会2002年发表的报告,将14个KIR功能基因的组合界定为抑制型KIR(L-KIR)基因组合型和非抑制型KIR(non-L-KIR)基因组合型。抑制型基因组合型是由多个抑制性KIR(L-KIR)基因(2DL1,2DL3,2DL4,3DL1,3DL2,3DL3)和单个激活性(S-KIR)基因(2DS4)组成的KIR基因组合型编为AA类型。而非抑制型基因组合的两种类型(BB,AB)为由多个L-KIR基因(2DL1,2DL3,2DL4,3DL1,3DL2,3DL3)与除2DS4外的S-KIR基因(2DS1,KIR-2DS2,KIR-2DS3,KIR-2DS5,KIR-3DS1)组成的KIR基因组合型编为BB类型;由多个L-KIR基因(2DL1,2DL3,2DL4,3DL1,3DL2,3DL3)和含有2DL4的多个S-KIR基因(2DS1,2DS2,2DS3,2SD4,2DS5,3DS1)组成的KIR基因组合型编为AB类型。
结果:24对供受者中AA类型基因组合型的供者9例,受者10例;BB类型基因组合型供者为3例,受者4例,AB类型基因组合型供者12例,受者10例。AA类型基因组合型受者术后急性排斥反应的发生率10%(1/10);BB和AB类型基因组合型的受者术后急性排斥反应的发生率64.29%(9/14),两组急性排斥反应的发生率呈显著差异(P＜0.05)。供者AA类型基因组合型受者术后急性排斥反应的发生率11.11%(1/9),供者BB和AB类型基因组合型的受者术后急性排斥反应的发生率60%(9/15)(P＜0.05)。供受者均AA/AA基因组合型配型的受者移植后急性排斥反应的发生率为0%(0/4);而供受者不是AA/AA基因组合型配型的受者术后急性排斥反应的发生率为50%(10/20)(P＞0.05)。
结论:AA类型基因组合型受者肾移植术后急性排斥反应的发生率低,对BB或AB类型基因组合型受者选择AA类型基因组合型的供肾能够降低急性排斥反应的发生率。提示抑制型基因组合型AA类型在肾移植早期可能主要传导抑制信号通路为主。
With the progress of the tissue matching technique in kidney transplantation, new immunosuppressive agent and biological agent used to clinic become nomal, which keep the supper-acute rejection(AR) away on the whole,meanwhile,the rate and strength of the AR is cut down.But in the same condition of tissue matching and immunosuppressive agent used,some patient occur AR.The AR not only occur graft failure in earlier period,but the one of the most important factor of the graft long term survival.This make to reduce AR after kidney transplantation and to prolong the live time of the graft become a important topic.beside the tissue matching,there may be orther transplantation immunity access play a role.The relationship of killer cell immunoglobulin-like receptor which is the ligand of the HLA in the surface of nature killer cell and part of effector T cells with transplantation AR have much attention.
KIR molecule belong to immuneglobulin superfamilly,express to the surface of the NK cell and part effector T cells.KIR Genes coding for them are found on chromosome 19q13.4,express codominance,owned 16 KIR gene,cotents 14function genes and 2silent genes.Its encoding proteinum KIR receptor is transmembrane glycoprotein,according to the side of cytoplasmic domain,KIRdivide to L-type and S-type,L-type transmit inhibitory signal,named inhibitory KIR;S-type transmit activate signal,named activatory KIR.KIR receptor can recognite and blind HLA-Ⅰantigen specificity,so transmit and regulate NK cell and part effector T cells kill target cell.According to the numbers of the immunoglobulin like domain extracellular region,KIR gene cord protein individe as KIR2D and KIR3D,KIR2D consist of KIR2DL1～L5,KIR2DS1～S5;KIR3D consist of KIR3DL1～L3 and KIR3DS1。
For example:inhibitory receptor KIR3DL1 have three immunoglobulin like domain and immunoreceptor tyrosine-based inhibitory motif(ITIM) activatory receptor KIR3DS1,its transmembrane domain has with positive charge residue that can bind specificity junct protein,no ITIM.inhibitory KIR receptor transmit inhibitor signal control NK cell kill target cell,activatory KIR receptor lack of ITIM,let activatory signal access form active NKcell and effective T cell kill target cell.
A NK cell may express multitude KIR3D and KIR3D molecule alone or at equal pace,likewise,can express multitude activatory or inhibitory receptor.generally,the ligand of KIR2D is HLA-Cw,and the ligand of KIR3D is HLA-A and HLA-B4. compared activatory receptor,inhibitory receptor have more closed affinity with HLA-Ⅰ,when activatory or inhibitory receptor recognite and bind the same HLA-Ⅰantigen,inhibitory effect play the main role.KIR bind corresponding HLA-Ⅰmay hame four results followed:1、When inhibitory KIR bind HLA-Ⅰand there has no activatory KIR bind it,cell isn't dissolve because inhibitory signal access was done;2、When activatory KIR bind corresponding HLA-Ⅰand there has no inhibitory KIR bind it,form activate signal,lead cell dissolve.3、If activatory or inhibitory receptor both bind HLA-Ⅰ,both signal access is make done,when activatory signal play the main role,NK cell still actived,lead target cell dissolve.4、If activatory or inhibitory receptor both bind HLA-Ⅰ,both signal access is make done,when inhibitory signal play the main role,or both signal access don't play,NK cell do not make effect.this is NK cell recognice nomal tissue.
At present,in clinic,tissue matching contains HLA-A、B、DR genotyping,PRA and CDC.Recent years,some foundation study of HLA biology and hemopoietic stem cell transplantation finding that HLA-Cw-KIR,HLA and its ligand KIR form differ immunity transmit signal and lead differ immunity regulate access in hemopoietic stem cell transplantation and tumor treatment.
The frequencies of KIR gene in different race and different individual is different, so the KIR genotype in individual may different.KIR gene is express codominanced, KIR genotype differ between individual,so in vivo NK cell and part effect T cell sufface KIR receptor type may differed,lead immunity transmit signal may deffered.Kidney transplantation is recipient accept donor's antigent,a series of immunity reaction aim to graft occurd necessarily.
Whether or not HLA-Ⅰ-KIR play the role at immune response in the AR on earlier period after kidney transplantation,this research review the frequencies that KIR genes in population and the distribution of its genotypes,analysis the correlation that inhibitory genotypes of kidney donor-recipient pair with AR.This article contains three chapters followed:
Chapter one The detection of killer cell immunoglobulin-like receptor KIR genes
Objective To investigate the KIR gene frenquencies of killer cell immunoglobulin-like receptor of uremia patients.
Methods Uremia patients were chosen to drawn venous blood According the KIR basic radical coded sequence that publication by IDP KIR sequence library(www.ebi.ac.uk/ipd/kir) on November 10,2006.Twenty-three pairs of primers were designed,whole were verification by BLAST software,which can recognize 16 KIR genes,contains 14 functional genes and 2 silent genes.In our unit,55 uremia patients who waiting for kidney transplantation.Analysis by polymerase chain recation-sequences specific primer,PCR-SSP,work out the KIR gene frenquencies of 55 uremia patients,compared with Korean,Japanese,Southern Asian.
Results Sixteen genes were observed in uremia patients,contains 14 functional genes(2DL1、2DL2、2DL3、2DL4、2DL5、3DL1、3DL2、3DL3、2DS1、2DS2、2DS3、2DS4、2DS5、3DS1)and 2 silent genes(2DP1,3DP1).
The frequencies(GF)of 2DL4,3DL2,3DL3 and 3DP1 are 1.00;2DL1,2DL3, 3DL1 and 2DS4 are 0.73～0.87;2DL2,2DS1,2DS2,2DS3 and 2DS5 are 0.11～ 0.25;2DL5,3DS1 and 2DP1 are 0.30～0.41.Compared the frequencies of uremia patients(GF 0.73～1.00 in KIR-2DL4,3DL1,3DL2,3DL3,2DS4) &(GF 0.11～0.34 in KIR-2DL2,2DL5,2DS1,2DS3,2DS5,3DS1)with Korean,Japanese, Southern Asian subjects,the difference were less than 0.20.In addition,the frequencies of KIR-2DL1 in uremia patients was lower than Japanese,2DS2 was lower than Southern Asian,and 2DL3 was higher than Southern Asain.
Conclusions All 16 known genes observed in uremia patients indicated that the KIR genes are polymorphic.The most frequent genes were 2DL4,3DL2,3DL3 and 3DP1;followed by 2DL1,2DL3,3DL1 and 2DS4;rare of 2DL2,2DS1, 2DS2,2DS3 and 2DS5.This study shows that there is a high concordance but variability in the frequent distributions of KIR gene among the uremia patients and Asian populations.
Chapter two Analysis of killer cell immunoglobulin-like receptor KIR genotypes
Objective To investigate the killer cell immunoglobulin-like receptor KIR genetypes distribution of population
Methods DNA samples from 67 randomly unrelated individuals in Chinese Han population were genotyped with PCR-SSP method and a comparison of frequencies of KIR genes were done with other populations.According the KIR basic radical coded sequence that publication by IDP KIR sequence library (www.ebi.ac.uk/ipd/kir) on November 10,2006.Twenty-three pairs of primers were designed,whole were verification by BLAST software,which can recognize 16 KIR genes and alliles.
Results 16 KIR genes were found in Chinese Han individual in this study, contains 14 functional genes(2DL1、2DL2、2DL3、2DL4、2DL5、3DL1、3DL2、3DL3、2DS1、2DS2、2DS3、2DS4、2DS5、3DS1)and 2 silent genes(2DP1,3DP1). There were 25 genetypes constitution by 14 functional genes were detected.among them the most frequent one was KIR-2DL1-2DL3-2DL4-3DL1-3DL2-3DL3- 2DS4(0.373),the other 24 were≤0.09.Comparing the Chinese Han KIR combinations with these of Japanese,Korean,Caucasians,there are 56 KIR genotypes summary. Analysis the KIR genotypes in the four populations,they are share 5 KIR genotypes, 8.93%of the KIR combinations were detected in all these populations;5.36%were detected in Chinese,Koreans and Caucasians;1.79%were only found in Chinese and Caucasians;In this study,16 kinds of new gene combinations were identified (28.58%).2 kinds of genotypes were only found in Japanese(3.57%);9 kinds of genotypes were only found in Korean(16.07%);and 16 kinds of genotypes were only found in Caucasians(28.58%).
Conclusions This study shows that Among 25 KIR genotypes in the 67 Chinese Han,only the distribution frequency of KIR-2DL1-2DL3-2DL4-3DL1-3DL2-3DL3-2DS4 was 0.373(4%),which is an inhibitable signal transduction pathway.We found one kind of KIR combination(KIR-2DLl-2DL3-2DL4-3DL1-3DL2-3DL3-2DS4) is the most frequent in all these populations(Chinese,Japanese, Koreans and Caucasians).
Chapter three Association between inhibitory KIR genotype and acute rejection after kidney transplantation
Objective To investigate the effect of inhibitory KIR genotypes(L-KIR,AA) on acute rejection(AR) after cadaveric kidney transplantation.
Mothods DNA samples from 24 donor-recipient pair were genotyped with PCR-SSP method and a comparison of frequencies of KIR genes were done with other populations.According the KIR basic radical coded sequence that publication by IDP KIR sequence library(www.ebi.ac.uk/ipd/kir) on November 10,2006. Twenty-three pairs of primers were designed,whole were verification by BLAST software,which can recognize 16 KIR that contains 14 functional genes(2DL1、2DL2、2DL3、2DL4、2DL5、3DL1、3DL2、3DL3、2DS1、2DS2、2DS3、2DS4、2DS5、3DS1)and 2 silent genes(2DP1,3DP1),reference to the report that make by Marsh in WHO-KIR Nomenklatur Kommission in 2002.It identify the 14 functional genes to inhibition genotype and non inhibition genotypes,inhibition genotype consist by some inhibitory KIR genes(2DL1,2DL3,2DL4,3DL1,3DL2,3DL3) and a activatory KIR gene(2DS4),named group AA.non inhibition genotypes content two group,group BB and AB.BB consist by some inhibitory KIR genes (2DL1,2DL3,2DL4,3DL1,3DL2,3DL3) and some activatory KIR genes(2DS1, 2DS2,2DS3,2DS5,3DS1)(no 2DS4);AB consist by some inhibitory KIR genes (2DL1,2DL3,2DL4,3DL1,3DL2,3DL3) and some activatory KIR genes(2DS1, 2DS2,2DS3,2SD4,2DS5,3DS1)(content 2DS4).
RESULTS:Of the 24 pairs,AA KIR genotype was found in 9 donors and 10 recipients;BB KIR genotype was found in 3 donors and 4 recipients;AB KIR genotype was observed in 12 donors and 10 recipients.AR occurred in 10%(1/10) of the recipients with AA KIR genotype and in 64.29%(9/14) of the recipients with BB & AB KIR genotype.The difference between the two groups was significant (P＜0.05).11.11%(1/9) of the donors with AA KIR genotype had AR while 60% (9/15) of the donors with BB & AB KIR genotypes suffered AR,with significant difference between the two groups(P＜0.05).0%(0/4) of the donors/recipients with AA/AA match had AR while 50%(10/20) of the donors/recipients with non-AA/AA match suffered AR,without significant difference(P＞0.05).
CONCLUSIONS:Recipients with AA KIR genotype tend to have a lower incidence of AR,while for recipients with BB & AB KIR genotypes,choice of a graft with AA KIR genotype may reduce the incidence of AR.These may be due to the possible mechanism that AA KIR genotype was characterized by inhibitory conducting signals after kidney transplantation early.
引文
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