Presentation is loading. Please wait.

Presentation is loading. Please wait.

HLA: matching and donor selection Dr Bronwen Shaw Consultant in haematopoietic cell transplantation Royal Marsden Hospital Anthony Nolan Trust.

Similar presentations


Presentation on theme: "HLA: matching and donor selection Dr Bronwen Shaw Consultant in haematopoietic cell transplantation Royal Marsden Hospital Anthony Nolan Trust."— Presentation transcript:

1 HLA: matching and donor selection Dr Bronwen Shaw Consultant in haematopoietic cell transplantation Royal Marsden Hospital Anthony Nolan Trust

2 Overview Why does HLA matter in transplantation? HLA Where is it found? What does it do? Tissue typing? What does the nomenclature mean and how do we classify ‘matching’ and ‘mismatching’? Polymorphism Some examples

3 Survival for CML Unrelated HCT: JMDP Tally Effect HCT Component Data

4 What is HLA? What is it for? Human Leukocyte Antigen Discovered: in mice (1937), humans (1954) Function: to present peptides to T cells, thus allowing elimination of foreign particles and recognition of self (so in transplants this has to be modulated)

5

6 4 Mb 3 Mb 2 Mb 1 Mb 0 Mb HLA-A HLA-C HLA-B HLA-DR HLA-DQ HLA-DP

7 The HLA Family A1A2 Cw7Cw5 B8B44

8 The HLA Family A1A2 Cw7Cw5 B8B44 A3A26 Cw7Cw8 B7B14

9 The HLA Family A1 Cw7 B8 A1A2 Cw7Cw5 B8B44 A3A26 Cw7Cw8 B7B14 A3 Cw7 B7

10 The HLA Family A1 Cw7 B8 A1A2 Cw7Cw5 B8B44 A3A26 Cw7Cw8 B7B14 A1A26 Cw7Cw8 B8B14 A3 Cw7 B7

11 The HLA Family A1 Cw7 B8 A1A2 Cw7Cw5 B8B44 A3A26 Cw7Cw8 B7B14 A1A26 Cw7Cw8 B8B14 A2 Cw5 B44 A3 Cw7 B7 A3 Cw7 B7

12 The HLA Family A1 Cw7 B8 A1A2 Cw7Cw5 B8 B44 A3A26 Cw7Cw8 B7B14 A1A26 Cw7Cw8 B8B14 A2 Cw5 B44 A3 Cw7 B7 A3 Cw7 B7 A2 Cw5 B44 A26 Cw8 B14

13 The HLA Family A1 Cw7 B8 A1A2 Cw7Cw5 B8B44 A3A26 Cw7Cw8 B7B14 A1A26 Cw7Cw8 B8B14 A2 Cw5 B44 A3 Cw7 B7 A3 Cw7 B7 A2 Cw5 B44 A26 Cw8 B14 A1 Cw7 B8 A3 Cw7 B7

14 The HLA Family A1 Cw7 B8 A1A2 Cw7Cw5 B8B44 A3A26 Cw7Cw8 B7B14 A1A26 Cw7Cw8 B8B14 A2 Cw5 B44 A3 Cw7 B7 A3 Cw7 B7 A2 Cw5 B44 A26 Cw8 B14 A1 Cw7 B8 A3 Cw7 B7

15 The HLA Family A1 Cw7 B8 A1A2 Cw7Cw5 B8B44 A3A26 Cw7Cw8 B7B14 A1A26 Cw7Cw8 B8B14 A2 Cw5 B44 A3 Cw7 B7 A3 Cw7 B7 A2 Cw5 B44 A26 Cw8 B14 A1 Cw7 B8 A3 Cw7 B7

16 The HLA Family A1 Cw7 B8 A1A2 Cw7Cw5 B8B44 A3A26 Cw7Cw8 B7B14 A1A26 Cw7Cw8 B8B14 A2 Cw5 B44 A3 Cw7 B7 A3 Cw7 B7 A2 Cw5 B44 A26 Cw8 B14

17 The HLA Family A1 Cw7 B8 A1A2 Cw7Cw5 B8B44 A3A26 Cw7Cw8 B7B14 A1A26 Cw7Cw8 B8B14 A2 Cw5 B44 A3 Cw7 B7 A3 Cw7 B7 A2 Cw5 B44 A26 Cw8 B14 A1 Cw7 B8 A3 Cw7 B7

18 MHC Sequencing Consortium, 1999 One of the most gene-dense regions of the genome 224 genes identified within the 3.6 Mb 40% of the genes have functions within the immune response HLA is the most polymorphic region in the human genome

19

20 Map of the human MHC on chromosome 6

21 1 L exon protein domain 5 TM 8 3'UT 67 CYT 234    Polymorphism located in exons 2 & 3 HLA Class I - found on all nucleated cells

22 Class I HLA-A

23 1 L exon protein domain 5 3'UT  -chain gene 234 TM/CYT 1 L exon protein domain 6 3'UT  -chain gene 3425     TM CYT Polymorphism located in exon 2 HLA Class II - restricted to cells of the immune system

24 Class II HLA-DR

25 HLA and Tissue Typing Cell

26 HLA and Tissue Typing Cell Serology-low resolution e.g. A2

27 HLA and Tissue Typing Cell Medium resolution ‘string’ e.g. A*0201/0205/0209/0240 SSP, SSOP High resolution (definitive) e.g. A* SBT

28 HLA Nomenclature Gene names HLA-A or HLA-DRB1 Antigen names A2 or DR1 Allele names A* or DRB1*

29 HLA Allele Nomenclature HLA - A * Locus Asterisk Allele family (serological where possible) Amino acid difference Non-coding (silent) polymorphism Intron, 3’ or 5’ polymorphism N = null L = low S = Sec. A = Abr. HLA - A * L

30 Low level of resolutionA*02 Medium level (string)A*0201/0205/0209/0240 High levelA* Level of resolution Antigen matched Allele matched Type is ONE OF these four: Antigen matched BUT do not know if allele matched

31 Using medium level resolution typing it is possible to exclude some but not all alleles from a group, hence the National Marrow Donor Program (NMDP) codes. B*1501 or B*1502=B*15AB B*1501/1502/1505/1515/1521/1545/1556/1570=B*15FGR This is important for donor selection i.e. you may be able to tell if a donor is definitely MISMATCHED but not matched Ambiguity

32 Numbers of HLA antigens and alleles New HLA Class I alleles per year 50 New HLA Class II alleles per year

33 Number of HLA Alleles June 2004/2006/2007 (http://www.ebi.ac.uk/imgt/hla/stats.html) HLA- A HLA- BHLA-C 325 (24) 592 (49)175 (9) 489/617830/960210/335 DRBDQA1 DQB1 DPA1DPB1 458 (20) (7) (DRB1 463/542)3478/ /127 MICATAP Figures in parenthesis indicate the number of serologically defined antigens at each locus.

34 Linkage Disequilibrium/ Haplotypes LD: Alleles occur together with a greater frequency than would be expected by chance –B/C strong, DR/DQ strong, A less strong, DP weak –e.g. B* % will be Cw*0701 –But B*1801 either Cw*0501, *0701 –e.g DRB1* will be DQB1*0602 –But DRB1*0401 either Cw*0301, *0302 Haplotype: A group of genes inherited together –e.g. A*0101,B*0801,Cw*0701,DRB1*0301,DQB1*0201

35 Examples for search coordinators and data managers

36 Example 1: VUD search Patient: –A*0101, B*0801, DRB1*0301 Finding a donor: –Common haplotype - therefore likely –Usually in strong LD - therefore ‘predictable’ –Even at low resolution (A1, B8, DR3) good chance of being matched

37 Example 1: Data entry Patient: –A*0101, B*0801, DRB1*0301 Donor: –A1, B8, DRB1 03: Antigenic match for A, B, DRB1 No data can be entered for C, DQB1, DPB1 No data can be entered for allele level matching –A*0101, B*0801, DRB1*0301: Allelic and antigenic match for A, B, DRB1 No data can be entered for C, DQB1, DPB1

38 Example 2: VUD search Patient: –A*0201, B*1801, DRB1*0401 Finding a donor: –Less strong LD - therefore ‘ NOT predictable’ i.e. equal chance of C being *0701, *0501, *1203; DQB1 50/50 chance of *0301, *0302 –At low resolution (A2, B18, DRB4) unable to predict this will match

39 Example 2: VUD search (cont) DonorA*02

40 Example 2: VUD search (cont) A*02

41 Example 2: VUD search (cont) A*02

42 Example 2: VUD search (cont) A*02

43 Example 2: VUD search (cont) A*02

44 Example 2: VUD search (cont) A*02

45 Example 2: VUD search (cont) A*02

46 Example 2: Data entry Patient: –A*0201, B*1801, DRB1*0401 Donor: –A2, B18, DRB1 04: Antigenic match for A, B, DRB1 No data can be entered for C, DQB1, DPB1 No data can be entered for allele level matching –A*0201, B*1801, DRB1*0401: Allelic and antigenic match for A, B, DRB1 No data can be entered for C, DQB1, DPB1 –A*0201/05, B*1801, DRB1*0401: Allelic and antigenic match for B, DRB1 Antigenic match for A BUT cannot say that this is an allelic match

47 Example 2: Data entry Patient: –A*0201, B*1801, DRB1*0401 Donor: –A2, B18, DRB1 04: Antigenic match for A, B, DRB1 No data can be entered for C, DQB1, DPB1 No data can be entered for allele level matching –A*0201, B*1801, DRB1*0401: Allelic and antigenic match for A, B, DRB1 No data can be entered for C, DQB1, DPB1 –A*0201/05, B*1801, DRB1*0401: Allelic and antigenic match for B, DRB1 Antigenic match for HLA-A BUT cannot say that this is an allelic match

48 Example 3: search and data patientdonorsearchdata A*0201/9207/920 9 Probable match (rare) Select donor Antigen match (probable allelic) B*3503 B*4403 B*3503 B*4403 Match Select donor Antigenic and allelic match Cw*0401/24 Cw*1601 Cw*0401/20/24 Cw*1601 Probable match (rare) Select donor Antigen match (probable allelic) DRB1*0701, DRB1*1501/18 DRB1*0701, DRB1*1501/18 Probable match (rare) Select donor Antigen match (probable allelic) DQB1*0202 DQB1*0602 DQB1*0202 DQB1*0602 Match Select donor Antigenic and allelic match Rare alleles: A*9207, *9209, Cw*0420, Cw*0424, DRB1*1518

49 Example 3: search and data patientdonorsearchdata A*0201/9207/920 9 Probable match (rare) Select donor Antigen match (probable allelic) B*3503 B*4403 B*3503 B*4403 Match Select donor Antigenic and allelic match Cw*0401/24 Cw*1601 Cw*0401/20/24 Cw*1601 Probable match (rare) Select donor Antigen match (probable allelic) DRB1*0701, DRB1*1501/18 DRB1*0701, DRB1*1501/18 Probable match (rare) Select donor Antigen match (probable allelic) DQB1*0202 DQB1*0602 DQB1*0202 DQB1*0602 Match Select donor Antigenic and allelic match Rare alleles: A*9207, *9209, Cw*0420, Cw*0424, DRB1*1518

50 Example 3: search and data patientdonorsearchdata A*0201/9207/920 9 Probable match (rare) Select donor Antigen match (probable allelic) B*3503 B*4403 B*3503 B*4403 Match Select donor Antigenic and allelic match Cw*0401/24 Cw*1601 Cw*0401/20/24 Cw*1601 Probable match (rare) Select donor Antigen match (probable allelic) DRB1*0701, DRB1*1501/18 DRB1*0701, DRB1*1501/18 Probable match (rare) Select donor Antigen match (probable allelic) DQB1*0202 DQB1*0602 DQB1*0202 DQB1*0602 Match Select donor Antigenic and allelic match Rare alleles: A*9207, *9209, Cw*0420, Cw*0424, DRB1*1518

51 Example 4: search and data patientdonorsearchdata A* /06 A* /16-22/24- 31/33/36-41 A* /06/07 A* /16-22/24- 31/33/36-42/44/45 Probable match - but not certain Antigen match Cannot report allelic status B*0801/05/07/10 B*4402/05/11/14 B*0801/05/07/10/12 B*4402/05/11/14 Probable match - but not certain Antigen match Cannot report allelic status Cw*0701/05/06/08/14 Cw*0401/03/04/05/06 /07 Cw*0701/05/06/08/14 Cw* Probable match (one antigen)- but not certain Definite mismatch Antigen match x1 Cannot report allelic status Antigen and allelic mm x1 DRB1*1301/40 DRB1*1401 DRB1*1301 DRB1*1401 Probable match - but not certain Antigen match x1 Cannot report allelic status Antigen and allelic mm x1 DQB1*0603/14 DQB1* DQB1*0603/14 DQB1* Probable match - but not certain Antigen match x1 Cannot report allelic status Antigen and allelic mm x1 Rare alleles: ???????????

52 Useful websites Anthony Nolan Trust: NMDP allele codes: index.html World Marrow Donor association: Bone marrow donor worldwide: HLA database:


Download ppt "HLA: matching and donor selection Dr Bronwen Shaw Consultant in haematopoietic cell transplantation Royal Marsden Hospital Anthony Nolan Trust."

Similar presentations


Ads by Google