造血干细胞移植的HLA配型
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杂合子基因
3 18
3 7
3 18
纯合子基因
表现型 单体型
患者 HLA-A3,11
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
How 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 mismatches • Try to avoid an antigen-level mismatch
造血干细胞移植的HLA配型
中国医学科学院血液病医院 杨栋林
HLA
HLA (human leucocyte antigen) system or MHC (major histocompatibility complex) is the name given to the highly polymorphic gene cluster region on chromosome 6 which codes for cell surface proteins involved in immune recognition.
Serologic Types (Antigen Names)
B 62 (15)
Protein (Broad specificity)*
Serologic type in order discovered, broad or split
*Not required
Allele (DNA) Names
100% 90% 80% S u r v i v a l 70% 60% 50% 40% 30% 20% 10% 0% 0 1 2 3 4 5 6 Years After Transplant 7 8 9 100%
0 mismatched loci (n = 791) 1 mismatched locus (n = 394) 2 mismatched loci (n = 172) 3+ mismatched loci (n = 65)
DP DQ DR
BC
A
The gene complex is subdivided into 2 regions
• Class 1 The A, B and C loci. These proteins are found on most nucleated cells and interact with CD8+ T lymphocytes. • 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.
谢谢！
The Minimum Acceptable Match in the NMDP
DP DQ DR BC A
6 Antigens (Loci): A, B and DR A and B: Intermediate level DR: Allele level At least 5 of 6 antigens must match
A* 0302
Gene followed by asterisk
Digits 1-2 = Similarity and/or serology Digits 3-4 = Order discovered
Impact of Mismatch on Survival
Factor A B C DRB1
What if there is no perfect match?
• Assume that HLA-A, -B, -C and -DRB1 are equally important
• Accept one allele mismatch over one antigen mismatch • Minimize the number of allele mismatches
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。
90% 80% 70% 60% 50% 40% 30% 20%
P-value < 0.0001
10% 0%
How many loci should we type?
Locus HLA-A HLA-B HLA-C HLA-DRB1 DRB3, 4 and 5 HLA-DQA1 and B1 HLA-DPA1 and B1 Recommendation Yes, allele level Yes, allele level Yes, allele level Yes, allele level Yes, for linkage DQB1 for linkage Unclear
DQ DP
RR 1.33 1.22 1.21 1.23
0.98 1.07
95% CI (1.15, 1.54) (1.06, 1.41) (1.06, 1.38) (1.04, 1.45)
(0.84, 1.14) (0.89, 1.27)
P-value 0.0002 0.007 0.005 0.01
P-value
0.03 < 0.0001 0.32 < 0.0001 0.02 0.02
B allele
B serologic DRB1 allele DR serologic
DQ/DP: Survival
DQ/DP Mismatching Is Not a Risk Factor 1 Year Group N A,B,C,DRB1 Allele Matched Survival
How many loci should I match?
Locus HLA-A HLA-B HLA-C HLA-DRB1 DRB3, 4 and 5 HLA-DQA1 and B1 HLA-DPA1 and B1 Recommendation Yes Yes Yes Yes Unknown Unclear Unclear
Serologic MM
N 108 683 631
452
Survival 39% ± 9% 39% ± 4% 29% ± 4%
23% ± 4%
* HLA-A, -B, -C, DRB1, DQA1, DQB1, DPA1 and DPB1
HLA-A, -B & -DR Serologically Matched Pairs number of allele mismatches HLA-A, -B, -C & -DR
父 A位点 B位点 24 35 a b A位点 11 B位点 13 b c 子1
父 母 兄1 兄2 HLA-A11,24 HLA-A3,HLA-3,11 HLA-3,11
母 11 13 3 18 c 11 13 b d 子2
B13,35 B7,18 B13,18 B7,13 B13,18
3 7 d 11 13 b c 子3（患者）
HLA Proteins Expressed on Cells
Class I A B C
Cell
Class II* DR DQ DP
*Only on some cell types
• MHC-Ⅰ • MHC-Ⅱ
CD8+ T cells CTL CD4+ T cells Th cell
CD8+ T cell MHCⅠ
0.80 0.48
Allele vs. Antigen Mismatch: Survival
Factor A allele A serologic
RR
1.26 1.44 1.09 1.51 1.23 1.51
95% CI
(1.02, 1.55) (1.20, 1.73) (0.92, 1.30) (1.23, 1.85) (1.04, 1.47) (1.05, 2.16)
DQA/B, DPA/B matched (16/16 match)
Hale Waihona Puke Baidu
108 683
51% + 9% 52% + 4%
Flomenberg, 2001
DQ and/or DP allele mismatched
Overall Survival by Matching Groups
Matching Group Matched at 8 loci [16/16] MM at DQ/DP only Allele MM at A,B,C or DR
3 18
3 7
3 18
纯合子基因
表现型 单体型
患者 HLA-A3,11
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
How 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 mismatches • Try to avoid an antigen-level mismatch
造血干细胞移植的HLA配型
中国医学科学院血液病医院 杨栋林
HLA
HLA (human leucocyte antigen) system or MHC (major histocompatibility complex) is the name given to the highly polymorphic gene cluster region on chromosome 6 which codes for cell surface proteins involved in immune recognition.
Serologic Types (Antigen Names)
B 62 (15)
Protein (Broad specificity)*
Serologic type in order discovered, broad or split
*Not required
Allele (DNA) Names
100% 90% 80% S u r v i v a l 70% 60% 50% 40% 30% 20% 10% 0% 0 1 2 3 4 5 6 Years After Transplant 7 8 9 100%
0 mismatched loci (n = 791) 1 mismatched locus (n = 394) 2 mismatched loci (n = 172) 3+ mismatched loci (n = 65)
DP DQ DR
BC
A
The gene complex is subdivided into 2 regions
• Class 1 The A, B and C loci. These proteins are found on most nucleated cells and interact with CD8+ T lymphocytes. • 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.
谢谢！
The Minimum Acceptable Match in the NMDP
DP DQ DR BC A
6 Antigens (Loci): A, B and DR A and B: Intermediate level DR: Allele level At least 5 of 6 antigens must match
A* 0302
Gene followed by asterisk
Digits 1-2 = Similarity and/or serology Digits 3-4 = Order discovered
Impact of Mismatch on Survival
Factor A B C DRB1
What if there is no perfect match?
• Assume that HLA-A, -B, -C and -DRB1 are equally important
• Accept one allele mismatch over one antigen mismatch • Minimize the number of allele mismatches
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。
90% 80% 70% 60% 50% 40% 30% 20%
P-value < 0.0001
10% 0%
How many loci should we type?
Locus HLA-A HLA-B HLA-C HLA-DRB1 DRB3, 4 and 5 HLA-DQA1 and B1 HLA-DPA1 and B1 Recommendation Yes, allele level Yes, allele level Yes, allele level Yes, allele level Yes, for linkage DQB1 for linkage Unclear
DQ DP
RR 1.33 1.22 1.21 1.23
0.98 1.07
95% CI (1.15, 1.54) (1.06, 1.41) (1.06, 1.38) (1.04, 1.45)
(0.84, 1.14) (0.89, 1.27)
P-value 0.0002 0.007 0.005 0.01
P-value
0.03 < 0.0001 0.32 < 0.0001 0.02 0.02
B allele
B serologic DRB1 allele DR serologic
DQ/DP: Survival
DQ/DP Mismatching Is Not a Risk Factor 1 Year Group N A,B,C,DRB1 Allele Matched Survival
How many loci should I match?
Locus HLA-A HLA-B HLA-C HLA-DRB1 DRB3, 4 and 5 HLA-DQA1 and B1 HLA-DPA1 and B1 Recommendation Yes Yes Yes Yes Unknown Unclear Unclear
Serologic MM
N 108 683 631
452
Survival 39% ± 9% 39% ± 4% 29% ± 4%
23% ± 4%
* HLA-A, -B, -C, DRB1, DQA1, DQB1, DPA1 and DPB1
HLA-A, -B & -DR Serologically Matched Pairs number of allele mismatches HLA-A, -B, -C & -DR
父 A位点 B位点 24 35 a b A位点 11 B位点 13 b c 子1
父 母 兄1 兄2 HLA-A11,24 HLA-A3,HLA-3,11 HLA-3,11
母 11 13 3 18 c 11 13 b d 子2
B13,35 B7,18 B13,18 B7,13 B13,18
3 7 d 11 13 b c 子3（患者）
HLA Proteins Expressed on Cells
Class I A B C
Cell
Class II* DR DQ DP
*Only on some cell types
• MHC-Ⅰ • MHC-Ⅱ
CD8+ T cells CTL CD4+ T cells Th cell
CD8+ T cell MHCⅠ
0.80 0.48
Allele vs. Antigen Mismatch: Survival
Factor A allele A serologic
RR
1.26 1.44 1.09 1.51 1.23 1.51
95% CI
(1.02, 1.55) (1.20, 1.73) (0.92, 1.30) (1.23, 1.85) (1.04, 1.47) (1.05, 2.16)
DQA/B, DPA/B matched (16/16 match)
Hale Waihona Puke Baidu
108 683
51% + 9% 52% + 4%
Flomenberg, 2001
DQ and/or DP allele mismatched
Overall Survival by Matching Groups
Matching Group Matched at 8 loci [16/16] MM at DQ/DP only Allele MM at A,B,C or DR