HLA: matching and donor selection

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
(No Transcript)
6
(No Transcript)
7
The HLA Family
A1
A2
Cw7
Cw5
B8
B44
8
The HLA Family
A1
A2
A3
A26
Cw7
Cw5
Cw7
Cw8
B8
B44
B7
B14
9
The HLA Family
A1
A2
A3
A26
Cw7
Cw5
Cw7
Cw8
B8
B44
B7
B14
A1
A3
Cw7
Cw7
B8
B7
10
The HLA Family
A1
A2
A3
A26
Cw7
Cw5
Cw7
Cw8
B8
B44
B7
B14
A1
A1
A26
A3
Cw7
Cw7
Cw8
Cw7
B8
B8
B14
B7
11
The HLA Family
A1
A2
A3
A26
Cw7
Cw5
Cw7
Cw8
B8
B44
B7
B14
A1
A1
A26
A2
A3
A3
Cw7
Cw7
Cw8
Cw5
Cw7
Cw7
B8
B8
B14
B44
B7
B7
12
The HLA Family
A1
A2
A3
A26
Cw7
Cw5
Cw7
Cw8
B8
B44
B7
B14
A1
A1
A26
A2
A3
A3
A2
A26
Cw7
Cw7
Cw8
Cw5
Cw7
Cw7
Cw5
Cw8
B8
B8
B14
B44
B7
B7
B44
B14
13
The HLA Family
A1
A2
A3
A26
Cw7
Cw5
Cw7
Cw8
B8
B44
B7
B14
A1
A1
A26
A2
A3
A3
A2
A26
A1
A3
Cw7
Cw7
Cw8
Cw5
Cw7
Cw7
Cw5
Cw8
Cw7
Cw7
B8
B8
B14
B44
B7
B7
B44
B14
B8
B7
14
The HLA Family
A1
A2
A3
A26
Cw7
Cw5
Cw7
Cw8
B8
B44
B7
B14
A1
A1
A26
A2
A3
A3
A2
A26
A1
A3
Cw7
Cw7
Cw8
Cw5
Cw7
Cw7
Cw5
Cw8
Cw7
Cw7
B8
B8
B14
B44
B7
B7
B44
B14
B8
B7
15
The HLA Family
A1
A2
A3
A26
Cw7
Cw5
Cw7
Cw8
B8
B44
B7
B14
A1
A1
A26
A2
A3
A3
A2
A26
A1
A3
Cw7
Cw7
Cw8
Cw5
Cw7
Cw7
Cw5
Cw8
Cw7
Cw7
B8
B8
B14
B44
B7
B7
B44
B14
B8
B7
16
The HLA Family
A1
A2
A3
A26
Cw7
Cw5
Cw7
Cw8
B8
B44
B7
B14
A1
A1
A26
A2
A3
A3
A2
A26
Cw7
Cw7
Cw8
Cw5
Cw7
Cw7
Cw5
Cw8
B8
B8
B14
B44
B7
B7
B44
B14
17
The HLA Family
A1
A2
A3
A26
Cw7
Cw5
Cw7
Cw8
B8
B44
B7
B14
A1
A3
Cw7
Cw7
B8
B7
A1
A1
A26
A2
A3
A3
A2
A26
Cw7
Cw7
Cw8
Cw5
Cw7
Cw7
Cw5
Cw8
B8
B8
B14
B44
B7
B7
B44
B14
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
(No Transcript)
20
Map of the human MHC on chromosome 6
21
HLA Class I - found on all nucleated cells
22

• Class I HLA-A

23
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
Serology-low resolution e.g. A2
Cell
27
HLA and Tissue Typing
Medium resolution string e.g.
A0201/0205/0209/0240 SSP, SSOP High resolution
(definitive) e.g. A02010101 SBT
Cell
28
HLA Nomenclature

• Gene names
• HLA-A or HLA-DRB1
• Antigen names
• A2 or DR1
• Allele names
• A020101 or DRB101010101

29
HLA Allele Nomenclature

HLA - A 24 02 01 01
HLA - A 24 02 01 02 L
30
Level of resolution

• Low level of resolution A02
• Medium level (string) A0201/0205/0209/0240
• High level A020101

31
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.
• B1501 or B1502 B15AB
• B1501/1502/1505/1515/1521/1545/1556/1570 B15F
  GR
• This is important for donor selection i.e. you
  may be able to tell if a donor is definitely
  MISMATCHED but not matched

32
Numbers of HLA antigens and alleles 1968 - 2004
120 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- 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
• MICA TAP
• 56 11
• 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. B0801 - 99 will be Cw0701
• But B1801 either Cw0501, 0701
• e.g DRB11501 - will be DQB10602
• But DRB10401 either Cw0301, 0302
• Haplotype A group of genes inherited together
• e.g. A0101,B0801,Cw0701,DRB10301,DQB10201

35
Examples for search coordinators and data managers
36
Example 1 VUD search

• Patient
• A0101, B0801, DRB10301
• 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
• A0101, B0801, DRB10301
• 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
• A0101, B0801, DRB10301 Allelic and antigenic
  match for A, B, DRB1
• No data can be entered for C, DQB1, DPB1

38
Example 2 VUD search

• Patient
• A0201, B1801, DRB10401
• 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)

• Donor A02

40
Example 2 VUD search (cont)

• A02

41
Example 2 VUD search (cont)

• A02

42
Example 2 VUD search (cont)

• A02

43
Example 2 VUD search (cont)

• A02

44
Example 2 VUD search (cont)

• A02

45
Example 2 VUD search (cont)

• A02

46
Example 2 Data entry

• Patient
• A0201, B1801, DRB10401
• 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
• A0201, B1801, DRB10401 Allelic and antigenic
  match for A, B, DRB1
• No data can be entered for C, DQB1, DPB1
• A0201/05, B1801, DRB10401 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
• A0201, B1801, DRB10401
• 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
• A0201, B1801, DRB10401 Allelic and antigenic
  match for A, B, DRB1
• No data can be entered for C, DQB1, DPB1
• A0201/05, B1801, DRB10401 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
Rare alleles A9207, 9209, Cw0420, Cw0424,
DRB11518
49
Example 3 search and data
Rare alleles A9207, 9209, Cw0420, Cw0424,
DRB11518
50
Example 3 search and data
Rare alleles A9207, 9209, Cw0420, Cw0424,
DRB11518
51
Example 4 search and data
Rare alleles ???????????
52
Useful websites

• Anthony Nolan Trust
• www.anthonynolan.org.uk
• NMDP allele codes http//bioinformatics.nmdp.org/
  HLA/Allele_Codes/Allele_Code_Lists/index.html
• World Marrow Donor association
• www.worldmarrow.org
• Bone marrow donor worldwide
• www.bmdw.org
• HLA database
• http//www.ebi.ac.uk/imgt/hla/