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HLA: matching and donor selection

HLA: matching and donor selection. Dr Bronwen Shaw Consultant in haematopoietic cell transplantation Royal Marsden Hospital Anthony Nolan Trust. Overview. Why does HLA matter in transplantation? HLA Where is it found? What does it do? Tissue typing?

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HLA: matching and donor selection

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

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

  6. The HLA Family A1 A2 Cw7 Cw5 B8 B44

  7. The HLA Family A1 A2 A3 A26 Cw7 Cw5 Cw7 Cw8 B8 B44 B7 B14

  8. The HLA Family A1 A2 A3 A26 Cw7 Cw5 Cw7 Cw8 B8 B44 B7 B14 A1 A3 Cw7 Cw7 B8 B7

  9. The HLA Family A1 A2 A3 A26 Cw7 Cw5 Cw7 Cw8 B8 B44 B7 B14 A1 A3 A1 A26 Cw7 Cw7 Cw7 Cw8 B8 B7 B8 B14

  10. The HLA Family A1 A2 A3 A26 Cw7 Cw5 Cw7 Cw8 B8 B44 B7 B14 A1 A3 A1 A26 A2 A3 Cw7 Cw7 Cw7 Cw8 Cw5 Cw7 B8 B7 B8 B14 B44 B7

  11. The HLA Family A1 A2 A3 A26 Cw7 Cw5 Cw7 Cw8 B8 B44 B7 B14 A1 A3 A1 A26 A2 A3 A2 A26 Cw7 Cw7 Cw7 Cw8 Cw5 Cw7 Cw5 Cw8 B8 B7 B8 B14 B44 B7 B44 B14

  12. The HLA Family A1 A2 A3 A26 Cw7 Cw5 Cw7 Cw8 B8 B44 B7 B14 A1 A3 A1 A26 A2 A3 A2 A26 A1 A3 Cw7 Cw7 Cw7 Cw8 Cw5 Cw7 Cw5 Cw8 Cw7 Cw7 B8 B7 B8 B14 B44 B7 B44 B14 B8 B7

  13. The HLA Family A1 A2 A3 A26 Cw7 Cw5 Cw7 Cw8 B8 B44 B7 B14 A1 A3 A1 A26 A2 A3 A2 A26 A1 A3 Cw7 Cw7 Cw7 Cw8 Cw5 Cw7 Cw5 Cw8 Cw7 Cw7 B8 B7 B8 B14 B44 B7 B44 B14 B8 B7

  14. The HLA Family A1 A2 A3 A26 Cw7 Cw5 Cw7 Cw8 B8 B44 B7 B14 A1 A3 A1 A26 A2 A3 A2 A26 A1 A3 Cw7 Cw7 Cw7 Cw8 Cw5 Cw7 Cw5 Cw8 Cw7 Cw7 B8 B7 B8 B14 B44 B7 B44 B14 B8 B7

  15. The HLA Family A1 A2 A3 A26 Cw7 Cw5 Cw7 Cw8 B8 B44 B7 B14 A1 A3 A1 A26 A2 A3 A2 A26 Cw7 Cw7 Cw7 Cw8 Cw5 Cw7 Cw5 Cw8 B8 B7 B8 B14 B44 B7 B44 B14

  16. The HLA Family A1 A2 A3 A26 Cw7 Cw5 Cw7 Cw8 B8 B44 B7 B14 A1 A3 Cw7 Cw7 B8 B7 A1 A3 A1 A26 A2 A3 A2 A26 Cw7 Cw7 Cw7 Cw8 Cw5 Cw7 Cw5 Cw8 B8 B7 B8 B14 B44 B7 B44 B14

  17. 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

  18. Map of the human MHC on chromosome 6

  19. Polymorphism located in exons 2 & 3 exon 1 2 3 4 5 6 7 8 protein a a a L TM CYT 3'UT domain HLA Class I - found on all nucleated cells

  20. Class I HLA-A

  21. Polymorphism located in exon 2 exon 1 2 3 4 5 -chain gene protein a1 a L TM/CYT 3'UT domain exon 1 2 3 4 5 6 b-chain gene protein 1  L TM CYT 3'UT domain HLA Class II - restricted to cells of the immune system

  22. Class II HLA-DR

  23. HLA and Tissue Typing Cell

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

  25. HLA and Tissue Typing Medium resolution ‘string’ e.g. A*0201/0205/0209/0240 SSP, SSOP High resolution (definitive) e.g. A*02010101 SBT Cell

  26. HLA Nomenclature • Gene names HLA-A or HLA-DRB1 • Antigen names A2 or DR1 • Allele names A*020101 or DRB1*01010101

  27. 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 * 24 02 01 01 HLA Allele Nomenclature HLA - A * 24 02 01 02 L

  28. Antigen matched Type is ONE OF these four: Antigen matched BUT do not know if allele matched Allele matched Level of resolution Low level of resolution A*02 Medium level (string) A*0201/0205/0209/0240 High level A*020101

  29. Ambiguity • 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

  30. Numbers of HLA antigens and alleles 1968 - 2004 120 New HLA Class I alleles per year 50 New HLA Class II alleles per year

  31. Number of HLA Alleles June 2004/2006/2007(http://www.ebi.ac.uk/imgt/hla/stats.html) HLA- A HLA- B HLA-C 325 (24) 592 (49) 175 (9) 489/617 830/960 210/335 DRB DQA1 DQB1 DPA1 DPB1 458 (20) 28 57 (7) 22 103 545 (DRB1 463/542) 34 78/87 23 125/127 MICATAP 56 11 Figures in parenthesis indicate the number of serologically defined antigens at each locus.

  32. 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*0801 - 99% will be Cw*0701 • But B*1801 either Cw*0501, *0701 • e.g DRB1*1501 - 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

  33. Examples for search coordinators and data managers

  34. 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

  35. 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

  36. 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

  37. Example 2: VUD search (cont) • Donor A*02

  38. Example 2: VUD search (cont) • A*02

  39. Example 2: VUD search (cont) • A*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: 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

  45. 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

  46. Example 3: search and data Rare alleles: A*9207, *9209, Cw*0420, Cw*0424, DRB1*1518

  47. Example 3: search and data Rare alleles: A*9207, *9209, Cw*0420, Cw*0424, DRB1*1518

  48. Example 3: search and data Rare alleles: A*9207, *9209, Cw*0420, Cw*0424, DRB1*1518

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