造血干细胞移植的HLA配型.ppt

造血干细胞移植的造血干细胞移植的HLA配型配型中国医学科学院血液病医院杨栋林HLAHLAHLA(human leucocyte antigen)system or MHCMHC(major histocompatibilitycomplex)is the name given to the highly polymorphic gene cluster region on chromosome 6 which codes for cell surface proteins involved in immune recognition.HLA,即人类主要组织相容性复合物(major histocompatibility complex,MHC),定位于人类6 号染色体短臂区域6p21.3,包括220 多个基因,大小4Mb 左右。其中许多基因编码免疫系统蛋白质,包括那些控制T 淋巴细胞和自然杀伤细胞反应的蛋白质。CDRABDQDPThe gene complex is subdivided into 2 regionsClass 1 Class 1 The A,B and C loci.These proteins are found on most nucleated cells and interact with CD8+T lymphocytes.Class 2 Class 2 Comprising of DR,DP,DQ loci present only on APC,such as B lymphocytes,monocytes,dendritic cells,macrophages and activated T lymphocytes.Interact with CD4+T lymphocytes.HLA Proteins Expressed on CellsCellClass IA B C Class II*DRDQDP*Only on some cell typesMHC-CD8+T cells CTLMHC-CD4+T cells Th cellMHCCD8+T cellb父 HLA-A11,24 B13,35母 HLA-A3,-B7,18兄1 HLA-3,11 B13,18兄2 HLA-3,11 B7,13患者 HLA-A3,11 B13,18111331813371113318bcb dc2435111333187abcdA位点B位点父母11子1子2子3（患者）A位点B位点杂合子基因杂合子基因纯合子基因纯合子基因表现型表现型单体型单体型基因型基因型不发生重组时，子代间两条染色体相同的占25，一条染色体相同的占50，两条染色体都不相同的占25。理论上有1/4的患者可找到供者。而寻找到配型完全相合的无关供者的概率只有1/10万。S 代表该等位基因的产物是可溶性HLA 分子,不存在于细胞表面;L 代表编码低表达抗原;N代表无效基因,该基因不产生相应的HLA 抗原分子B62(15)Serologic Types(Antigen Names)ProteinSerologic type in order discovered,broad or split*Not required(Broad specificity)*Allele(DNA)NamesGene followed by asteriskDigits 1-2=Similarity and/or serologyDigits 3-4=Order discovered0302A*FactorRR95%CIP-valueA1.33(1.15,1.54)0.0002B 1.22(1.06,1.41)0.007C1.21(1.06,1.38)0.005DRB11.23(1.04,1.45)0.01DQ0.98(0.84,1.14)0.80DP1.07(0.89,1.27)0.48Impact of Mismatch on SurvivalFactorRR95%CIP-valueA allele1.26(1.02,1.55)0.03A serologic1.44(1.20,1.73)0.0001B allele1.09(0.92,1.30)0.32B serologic1.51(1.23,1.85)0.0001DRB1 allele1.23(1.04,1.47)0.02DR serologic1.51(1.05,2.16)0.02Allele vs.Antigen Mismatch:SurvivalDQ/DP:SurvivalDQ/DP Mismatching Is Not a Risk FactorFlomenberg,2001GroupA,B,C,DRB1 Allele MatchedN1 Year SurvivalDQA/B,DPA/B matched(16/16 match)10851%+9%DQ and/or DP allele mismatched68352%+4%Overall Survival by Matching GroupsMatching Group N SurvivalMatched at 8 loci 16/16 10839%9%MM at DQ/DP only68339%4%Allele MM at A,B,C or DR63129%4%Serologic MM45223%4%*HLA-A,-B,-C,DRB1,DQA1,DQB1,DPA1 and DPB1HLA-A,-B&-DR Serologically Matched Pairsnumber of allele mismatches HLA-A,-B,-C&-DR1 mismatched locus(n=394)0 mismatched loci(n=791)2 mismatched loci(n=172)3+mismatched loci(n=65)P-value 0.0001How many loci should we type?LocusRecommendation HLA-A Yes,allele level HLA-B Yes,allele level HLA-C Yes,allele level HLA-DRB1 Yes,allele level DRB3,4 and 5 Yes,for linkage HLA-DQA1 and B1 DQB1 for linkage HLA-DPA1 and B1 UnclearHow many loci should I match?LocusRecommendation HLA-A Yes HLA-B Yes HLA-C Yes HLA-DRB1 Yes DRB3,4 and 5 Unknown HLA-DQA1 and B1 Unclear HLA-DPA1 and B1 UnclearThe Minimum Acceptable Matchin the NMDPCDRABDQDP6 Antigens(Loci):A,B and DRA and B:Intermediate levelDR:Allele levelAt least 5 of 6 antigens must matchHow do we search for the best donor?Strategy:Search for an allele matched donor at HLA-A,-B,-C and DRB1(8 of 8 allele match)Minimize the number of allele-level mismatchesTry to avoid an antigen-level mismatchWhat if there is no perfect match?Assume that HLA-A,-B,-C and-DRB1 are equally importantAccept one allele mismatch over one antigen mismatch Minimize the number of allele mismatches谢谢！